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  • 1.
    Benetkiewicz, Magdalena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Díaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jankowski, Michal
    Bala, Dariusz
    Hoffman, Jacek
    Srutek, Ewa
    Laskowski, Ryszard
    Zegarski, Wojciech
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 29, no 4, p. 935-945Article in journal (Refereed)
    Abstract [en]

    Breast cancer is a common malignancy and the second most frequent cause of death among women. Our aim was to perform DNA copy number profiling of 22q in breast tumors using a methodology which is superior, as compared to the ones applied previously. We studied 83 biopsies from 63 tumors obtained from 60 female patients. A general conclusion is that multiple distinct patterns of genetic aberrations were observed, which included deletion(s) and/or gain(s), ranging in size from affecting the whole chromosome to only a few hundred kb. Overall, the analysis revealed genomic imbalances of 22q in 22% (14 out of 63) of tumors. The predominant profile (11%) was monosomy 22. The smallest identified candidate region, in the vicinity of telomere of 22q, encompasses approximately 220 kb and was involved in all but one of the tumors with aberrations on chromosome 22. This segment is dense in genes and contains 11 confirmed and one predicted gene. The availability of multiple biopsies from a single tumor provides an excellent opportunity for analysis of possible intra-tumor differences in genetic profiles. In 15 tumors we had access to two or three biopsies derived from the same lesion and these were studied independently. Four out of 15 (26.6%) tumors displayed indications of clonal intra-tumor genotypic differences, which should be viewed as a high number, considering that we studied in detail only a single human chromosome. Our results open up several avenues for continued genetic research of breast cancer.

  • 2. Bruder, Carl E G
    et al.
    Piotrowski, Arkadiusz
    Gijsbers, Antoinet A C J
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Erickson, Stephen
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandgren, Johanna
    von Tell, Desiree
    Poplawski, Andrzej
    Crowley, Michael
    Crasto, Chiquito
    Partridge, E Christopher
    Tiwari, Hemant
    Allison, David B
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    van Ommen, Gert-Jan B
    Boomsma, Dorret I
    Pedersen, Nancy L
    den Dunnen, Johan T
    Wirdefeldt, Karin
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles2008In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 82, no 3, p. 763-71Article in journal (Refereed)
    Abstract [en]

    The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.

  • 3.
    Buckley, Patrick G
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mantripragada, Kiran K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Benetkiewicz, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tapia-Paez, Isabel
    Diaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ali, Haider
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jarbo, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Bustos, Cecilía
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hirvela, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sinder Wilén, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fransson, Ingegerd
    Thyr, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johnsson, Britt-Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bruder, Carl E G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hergersberg, Martin
    Mandahl, Nils
    Blennow, Elisabeth
    Wedell, Anna
    Beare, David M
    Collins, John E
    Dunham, Ian
    Albertson, Donna
    Pinkel, Daniel
    Bastian, Boris C
    Faruqi, A Fawad
    Lasken, Roger S
    Ichimura, Koichi
    Collins, V Peter
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    A full-coverage, high-resolution human chromosome 22 genomic microarrayfor clinical and research applications2002In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 11, no 25, p. 3221-3229Article in journal (Refereed)
    Abstract [en]

    We have constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number variation. This chromosome 22 array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb. To demonstrate the utility of the array, we have applied it to profile acral melanoma, dermatofibrosarcoma, DiGeorge syndrome and neurofibromatosis 2. We accurately diagnosed homozygous/heterozygous deletions, amplifications/gains, IGLV/IGLC locus instability, and breakpoints of an imbalanced translocation. We further identified the 14-3-3 eta isoform as a candidate tumor suppressor in glioblastoma. Two significant methodological advances in array construction were also developed and validated. These include a strictly sequence defined, repeat-free, and non-redundant strategy for array preparation. This approach allows an increase in array resolution and analysis of any locus; disregarding common repeats, genomic clone availability and sequence redundancy. In addition, we report that the application of phi29 DNA polymerase is advantageous in microarray preparation. A broad spectrum of issues in medical research and diagnostics can be approached using the array. This well annotated and gene-rich autosome contains numerous uncharacterized disease genes. It is therefore crucial to associate these genes to specific 22q-related conditions and this array will be instrumental towards this goal. Furthermore, comprehensive epigenetic profiling of 22q-located genes and high-resolution analysis of replication timing across the entire chromosome can be studied using our array.

  • 4.
    Buckley, Patrick G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mantripragada, Kiran K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Di­az de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hansson, Caisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kiss, Hajnalka
    Vetrie, David
    Ernberg, Ingemar T.
    Nordenskjöld, Magnus
    Bolund, Lars
    Sainio, Markku
    Rouleau, Guy A.
    Niimura, Michihito
    Wallace, Andrew J.
    Evans, D. Gareth R.
    Grigelionis, Gintautas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 22005In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 26, no 6, p. 540-9Article in journal (Refereed)
    Abstract [en]

    Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.

  • 5. Buckley, Patrick G.
    et al.
    Walsh, Sarah H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Langford, Cordelia F.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genome-wide microarray-based comparative genomic hybridization analysis of lymphoplasmacytic lymphomas reveals heterogeneous aberrations2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 9, p. 1528-34Article in journal (Refereed)
    Abstract [en]

    Lymphoplasmacytic lymphoma (LPL) is not a sharply delineated lymphoma entity, either morphologically, phenotypically, or clinically. The diagnosis is often made by excluding other small cell lymphomas with plasmacytic differentiation, thus a genetic diagnostic marker would be of great benefit. Conventional cytogenetic techniques have previously demonstrated a deletion of 6q in a proportion of cases, varying from 7 to 55%. In this report, we apply array-based comparative genomic hybridization on 11 LPL samples. Genomic aberrations were detected in 9 of 11 cases, and included gains and losses. In general, the number of genetic aberrations was relatively low (two to three abnormalities per case). Recurrent aberrations detected were deletion of 6q (two cases), deletion of chromosome 17 (two cases), gain of 3q (two cases), and gain of chromosome 7 (two cases). This report not only confirms the reported loss of 6q in a proportion of cases but also highlights the genetic heterogeneity of LPL, in accordance with the known immunophenotypical, morphological, and clinical diversity of the disease.

  • 6.
    Buckley, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jarbo, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mathiesen, Tiit
    Scott, Carol
    Gregory, Simon
    Langford, Cordelia
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 7, p. 2653-2661Article in journal (Refereed)
    Abstract [en]

    Meningiomas are common neoplasms of the meninges lining of the central nervous system. Deletions of 1p have been established as important for the initiation and/or progression of meningioma. The rationale of this array-CGH study was to characterize copy number imbalances of chromosome 1 in meningioma, using a full-coverage genomic microarray containing 2,118 distinct measurement points. In total, 82 meningiomas were analyzed, making this the most detailed analysis of chromosome 1 in a comprehensive series of tumors. We detected a broad range of aberrations, such as deletions and/or gains of various sizes. Deletions were the predominant finding and ranged from monosomy to a 3.5-Mb terminal 1p homozygous deletion. Although multiple aberrations were observed across chromosome 1, every meningioma in which imbalances were detected harbored 1p deletions. Tumor heterogeneity was also observed in three recurrent meningiomas, which most likely reflects a progressive loss of chromosomal segments at different stages of tumor development. The distribution of aberrations supports the existence of at least four candidate loci on chromosome 1, which are important for meningioma tumorigenesis. In one of these regions, our results already allow the analysis of a number of candidate genes. In a large series of cases, we observed an association between the presence of segmental duplications and deletion breakpoints, which suggests their role in the generation of these tumor-specific aberrations. As 1p is the site of the genome most frequently affected by tumor-specific aberrations, our results indicate loci of general importance for cancer development and progression.

  • 7.
    Cetinkaya, Cihan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Martinsson, Tommy
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Trager, Catarina
    Kogner, Per
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    de Stahl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hedborg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, p. 231-Article in journal (Refereed)
    Abstract [en]

    Background: Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling. Methods: Based on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher's exact test, Bayes moderated t-test, independent samples t-test, and correlation analysis. Results: MNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q-tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p<0.001). Furthermore, in the 11q-tumor group a positive correlation was seen between the number of segmental aberrations and the age at diagnosis (Pearson Correlation 0.606; p=0.037). Among nonMNA/non11q-tumors (n=6), one tumor displayed amplicons on 11q and 12q and three others bore evidence of progression from low-risk tumors due to retrospective evidence of disease six years before diagnosis, or due to tumor profiles with high proportions of numerical chromosomal aberrations. An early age at diagnosis of MNA neuroblastomas was verified by registry data, with an average of 29.2 months for 43 cases that were not included in the present study. Conclusion: MNA and segmental 11q loss define two major genetic variants of unfavorable neuroblastoma with apparent differences in their pace of tumor evolution and in genomic integrity. Other possible, but less common, routes in the development of aggressive tumors are progression of low-risk infant-type lesions, and gene amplifications other than MYCN. Knowledge on such nosological diversity of aggressive neuroblastoma might influence future strategies for therapy.

  • 8.
    Chase, A.
    et al.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Leung, W.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Tapper, W.
    Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Jones, A. V.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Knoops, L.
    Clin Univ St Luc, Hematol Unit, B-1200 Brussels, Belgium.;Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium..
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Guglielmelli, P.
    Univ Florence, Dept Expt & Clin Med, Lab Congiunto MMPC, Florence, Italy..
    Zoi, K.
    Acad Athens, Biomed Res Fdn, Haematol Res Lab, Athens, Greece..
    Hall, V.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Chiecchio, L.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England..
    Eder-Azanza, L.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England..
    Bryant, C.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Docherty, L.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    White, H. E.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Score, J.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Mackay, D. J. G.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Vannucchi, A. M.
    Univ Florence, Dept Expt & Clin Med, Lab Congiunto MMPC, Florence, Italy..
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cross, N. C. P.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 10, p. 2069-2074Article in journal (Refereed)
    Abstract [en]

    Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n = 7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P < 0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r = 0.76; P = 0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n = 11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.

  • 9.
    Chase, Andrew
    et al.
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Pellagatti, Andrea
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Singh, Shalini
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Score, Joannah
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Tapper, William J.
    Univ Southampton, Fac Med, Southampton, Hants, England.
    Lin, Feng
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Hoade, Yvette
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Bryant, Catherine
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Trim, Nicola
    Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Lab, Birmingham, W Midlands, England.
    Yip, Bon Ham
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Zoi, Katerina
    Acad Athens, Biomed Res Fdn, Haematol Res Lab, Athens, Greece.
    Rasi, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Beijer Laboratory of Genome Research, Uppsala University,Uppsala, Sweden.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Boultwood, Jacqueline
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Cross, Nicholas C. P.
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia2019In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 5, p. 1184-1194Article in journal (Refereed)
    Abstract [en]

    Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1-6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.

  • 10.
    Cunningham, Janet L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Díaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Janson, Eva T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors2011In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 50, no 2, p. 82-94Article in journal (Refereed)
    Abstract [en]

    Serotonin producing endocrine carcinoma of small intestine (ileal carcinoid) is a clinically distinct endocrine tumor. It is generally considered as a sporadic disease and its molecular etiology is poorly understood. We report comprehensive clinical and molecular studies of 55 sporadic and familial patients diagnosed with this condition. Nine pedigrees encompassing 23 affected subjects were established, consistent with autosomal dominant mode of inheritance. Familial and sporadic patients demonstrated indistinguishable clinical pictures. Molecular analyses of 61 tumors from 45 individuals, including eight familial and 37 sporadic patients, aimed at determination of global copy number aberrations using BAC and Illumina SNP arrays and gene expression profiling by Affymetrix chips. Chromosome 18 aberrations were identified in both sporadic and in familial tumors; 100% vs. 38%, respectively. Other, less frequent aberrations were also common for both groups. Global expression profiles revealed no differentially expressed genes. Frequent gain of chromosome 7 was exclusively observed in metastases, when patient matched primary tumors and metastases were compared. Notably, the latter aberration correlated with solid growth pattern morphology (P < 0.01), a histopathological feature that has previously been related to worse prognosis. The clinical and molecular similarities identified between sporadic and familial cases suggest a common pathogenetic mechanism involved in tumor initiation. The familial variant of ileal carcinoid represents a previously unrecognized autosomal dominant inherited tumor disease, which we propose to call Familial Ileal Endocrine Carcinoma (FIEC). Our findings indicate the location of a FIEC tumor suppressor gene near the telomere of 18q, involved in development of inherited and sporadic tumors.

  • 11.
    Danielsson, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Moghadam, Behrooz Torabi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rychlicka-Buniowska, Edyta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland.
    Jaszczyński, Janusz
    Department of Urology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Kraków Branch, Kraków, Poland.
    Heintz, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Beijer Laboratory of Genome Research, Uppsala, Sweden.
    Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

  • 12. Darai-Ramqvist, Eva
    et al.
    Díaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandlund, Agneta
    Mantripragada, Kiran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klein, George
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Imreh, Stefan
    Kost-Alimova, Maria
    Array-CGH and multipoint FISH to decode complex chromosomal rearrangements2006In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 7, p. 330-Article in journal (Refereed)
    Abstract [en]

    Background: Recently, several high-resolution methods of chromosome analysis have been developed. It is important to compare these methods and to select reliable combinations of techniques to analyze complex chromosomal rearrangements in tumours. In this study we have compared array-CGH (comparative genomic hybridization) and multipoint FISH (mpFISH) for their ability to characterize complex rearrangements on human chromosome 3 (chr3) in tumour cell lines. We have used 179 BAC/PAC clones covering chr3 with an approximately 1 Mb resolution to analyze nine carcinoma lines. Chr3 was chosen for analysis, because of its frequent rearrangements in human solid tumours. Results: The ploidy of the tumour cell lines ranged from near-diploid to near-pentaploid. Chr3 locus copy number was assessed by interphase and metaphase mpFISH. Totally 53 chr3 fragments were identified having copy numbers from 0 to 14. MpFISH results from the BAC/PAC clones and array-CGH gave mainly corresponding results. Each copy number change on the array profile could be related to a specific chromosome aberration detected by metaphase mpFISH. The analysis of the correlation between real copy number from mpFISH and the average normalized inter-locus fluorescence ratio (ANILFR) value detected by array-CGH demonstrated that copy number is a linear function of parameters that include the variable, ANILFR, and two constants, ploidy and background normalized fluorescence ratio. Conclusion: In most cases, the changes in copy number seen on array-CGH profiles reflected cumulative chromosome rearrangements. Most of them stemmed from unbalanced translocations. Although our chr3 BAC/PAC array could identify single copy number changes even in pentaploid cells, mpFISH provided a more accurate analysis in the dissection of complex karyotypes at high ploidy levels.

  • 13.
    De Bustos, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Stahl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mantripragada, Kiran K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Buckley, Patrick G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Darai, Eva
    Hansson, Caisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grigelionis, Gintautas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Analysis of copy number variation in normal human population within a region containing complex segmental duplications on 22q11 using high resolution array-CGH2006In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 88, no 2, p. 152-162Article in journal (Refereed)
    Abstract [en]

    A previously detected copy number polymorphism (Ep CNP) in patients affected with neuroectodermal tumors led us to investigate its frequency and length in the normal population. For this purpose, a program called Sequence Allocator was developed and applied for the construction of an array that consisted of unique and duplicated fragments, allowing the assessment of copy number variation within regions of segmental duplications. The average resolution of this array was 11 kb and we determined the size of the Ep CNP to be 290 kb. Analysis of normal controls identified 7.7 and 7.1% gains in peripheral blood and lymphoblastoid cell line (LCL) DNA, respectively, while deletions were found only in the LCL group (7.1%). This array platform allows the detection of DNA copy number variation within regions of pronounced genomic complexity, which constitutes an improvement over available technologies.

  • 14.
    De Bustos, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ramos, Edward
    Young, Janet M.
    Tran, Robert K.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Langford, Cordelia F.
    Eichler, Evan E.
    Hsu, Li
    Henikoff, Steve
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Trask, Barbara J.
    Tissue-specific variation in DNA methylation levels along human chromosome 12009In: Epigenetics & Chromatin, ISSN 1756-8935, Vol. 2, p. 7-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Most methods to scan the genome in different tissues for differentially methylated sites have focused on the methylation of CpGs in CpG islands, which are concentrations of CpGs often associated with gene promoters. RESULTS: Here, we use a methylation profiling strategy that is predominantly responsive to methylation differences outside of CpG islands. The method compares the yield from two samples of size-selected fragments generated by a methylation-sensitive restriction enzyme. We then profile nine different normal tissues from two human donors relative to spleen using a custom array of genomic clones covering the euchromatic portion of human chromosome 1 and representing 8% of the human genome. We observe gross regional differences in methylation states across chromosome 1 between tissues from the same individual, with the most striking differences detected in the comparison of cerebellum and spleen. Profiles of the same tissue from different donors are strikingly similar, as are the profiles of different lobes of the brain. Comparing our results with published gene expression levels, we find that clones exhibiting extreme ratios reflecting low relative methylation are statistically enriched for genes with high expression ratios, and vice versa, in most pairs of tissues examined. CONCLUSION: The varied patterns of methylation differences detected between tissues by our methylation profiling method reinforce the potential functional significance of regional differences in methylation levels outside of CpG islands.

  • 15.
    de Ståhl, Teresita Díaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Piotrowski, Arkadiusz
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bogdan, Adam
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Poplawski, Andrzej
    von Tell, Desiree
    Hansson, Caisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Elshafie, Amir I.
    Elghazali, Gehad
    Imreh, Stephan
    Nordenskjöld, Magnus
    Upadhyaya, Meena
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bruder, Carl E. G.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array2008In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 29, no 3, p. 398-408Article in journal (Refereed)
    Abstract [en]

    To further explore the extent of structural large-scale variation in the human genome, we assessed copy number variations (CNVs) in a series of 71 healthy subjects from three ethnic groups. CNVs were analyzed using comparative genomic hybridization (CGH) to a BAC array covering the human genome, using DNA extracted from peripheral blood, thus avoiding any culture-induced rearrangements. By applying a newly developed computational algorithm based on Hidden Markov modeling, we identified 1,078 autosomal CNVs, including at least two neighboring/overlapping BACs, which represent 315 distinct regions. The average size of the sequence polymorphisms was approximately 350 kb and involved in total approximately 117 Mb or approximately 3.5% of the genome. Gains were about four times more common than deletions, and segmental duplications (SDs) were overrepresented, especially in larger deletion variants. This strengthens the notion that SDs often define hotspots of chromosomal rearrangements. Over 60% of the identified autosomal rearrangements match previously reported CNVs, recognized with various platforms. However, results from chromosome X do not agree well with the previously annotated CNVs. Furthermore, data from single BACs deviating in copy number suggest that our above estimate of total variation is conservative. This report contributes to the establishment of the common baseline for CNV, which is an important resource in human genetics.

  • 16. Descartes, Maria
    et al.
    Franklin, Judy
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Bruder, Carl E. G.
    Dumanski, Jan P.
    Carroll, Andrew J.
    Mikhail, Fady M.
    Distal 22q11.2 microduplication encompassing the BCR gene2008In: American journal of medical genetics. Part A, ISSN 1552-4825, Vol. 146A, no 23, p. 3075-3081Article in journal (Refereed)
    Abstract [en]

    Chromosome 22 band q11.2 has been recognized to be highly susceptible to subtle microdeletions and microduplications, which have been attributed to the presence of several large segmental duplications; also known as low copy repeats (LCRs). These LCRs function as mediators of non-allelic homologous recombination (NAHR), which results in these chromosomal rearrangements as a result of unequal crossover. The four centromeric LCRs at proximal 22q11.2 have been previously implicated in recurrent chromosomal rearrangements including the DiGeorge/Velocardiofacial syndrome (DG/VCFs) microdeletion and its reciprocal microduplication. Recently, we and others have demonstrated that the four telomeric LCRs at distal 22q11.2 are causally implicated in a newly recognized recurrent distal 22q11.2 microdeletion syndrome in the region immediately telomeric to the DG/VCFs typically deleted region. Here we report on the clinical, cytogenetic, and array CGH studies of a 4.5-year-old girl with history of failure to thrive, developmental delay (DD), and relative macrocephaly. She carries a paternally inherited approximately 2.1 Mb microduplication at distal 22q11.2, which spans approximately 34 annotated genes, and is flanked by two of the four telomeric 22q11.2 LCRs. We conclude that the four telomeric LCRs at distal 22q11.2 can mediate both deletions and duplications in this genomic region. Both deletions and duplication of this region present with subtle clinical features including mild to moderate mental retardation, DD, and mild dysmorphic features.

  • 17.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lambert, Jean-Charles
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grenier-Boley, Benjamin
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Broad Inst MIT, Cambridge, MA 02142 USA.;Harvard Univ, Cambridge, MA 02142 USA..
    Campion, Dominique
    Rouen Univ Hosp, INSERM, CNR MAJ, U1079, F-76031 Rouen, France..
    Dufouil, Carole
    Victor Segalen Univ, INSERM, U708, F-33076 Bordeaux, France..
    Pasquier, Florence
    Univ Lille, CNR MAJ, Inserm 1171, F-59000 Lille, France.;CHU Lille, F-59000 Lille, France..
    Amouyel, Philippe
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 98, no 6, p. 1208-1219Article in journal (Refereed)
    Abstract [en]

    Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

  • 18.
    Dumanski, Jan P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rasi, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ali, Abir S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Sorbye, Halfdan
    Grønbæk, Henning
    Cunningham, Janet L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 8, p. 427-443Article in journal (Refereed)
    Abstract [en]

    The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

  • 19.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Mikael
    Södertörn University, School of Life Sciences, Biology, Huddinge, Sweden.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Magnusson, Patrik K. E.
    Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
    Lindgren, Cecilia M.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
    Morris, Andrew P.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;Department of Biostatistics, University of Liverpool, Liverpool, UK.
    Cesarini, David
    Center for Experimental Social Science, New York University, New York, NY 10012, USA.
    Johannesson, Magnus
    Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mutagenesis: smoking is associated with mosaic loss of chromosome Y2015In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6217, p. 81-83Article in journal (Refereed)
    Abstract [en]

    Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.

  • 20.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Faculty of Pharmacy, Medical University of Gdansk, Poland.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Beijer Laboratory of Genome Research, Uppsala University.
    Loss of Chromosome Y in Leukocytes and Major Cardiovascular Events2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 4Article in journal (Other academic)
  • 21.
    Forsberg, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Absher, Devin
    Dumanski, Jan Piotr
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime2013In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, no 1, p. 1-10Article, review/survey (Refereed)
    Abstract [en]

    The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease-the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders.

  • 22.
    Forsberg, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Absher, Devin
    Dumanski, Jan Piotr
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime (Reprinted from vol 50, pg 1-10, 2013)2013In: Postgraduate medical journal, ISSN 0032-5473, E-ISSN 1469-0756, Vol. 89, no 1053, p. 417-426Article, review/survey (Refereed)
    Abstract [en]

    The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease-the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders.

  • 23.
    Forsberg, Lars A.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gisselsson, David
    Departments of Clinical Genetics and Oncology- Pathology, Skåne Regional and University Laboratories, Lund University, Lund SE-22184, Sweden..
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mosaicism in health and disease — clones picking up speed2017In: Nature reviews genetics, ISSN 1471-0056, E-ISSN 1471-0064, Vol. 18, no 2, p. 128-142Article, review/survey (Refereed)
    Abstract [en]

    Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.

  • 24.
    Forsberg, Lars A.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala Univ, Beijer Lab Genome Res, Uppsala, Sweden.
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rychlicka-Buniowska, Edyta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Danielsson, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moghadam, Behrooz Torabi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lind, Lars
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Med Univ Gdansk, Fac Pharm, Gdansk, Poland.
    Mosaic loss of chromosome Y in leukocytes matters2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 4-7Article in journal (Other academic)
  • 25.
    Forsberg, Lars A.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rasi, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Malmqvist, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pasupulati, Saichand
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pakalapati, Geeta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandgren, Johanna
    de Stahl, Teresita Diaz
    Zaghlool, Ammar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Score, Joannah
    Cross, Nicholas C. P.
    Absher, Devin
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Lindgren, Cecilia M.
    Morris, Andrew P.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 6, p. 624-628Article in journal (Refereed)
    Abstract [en]

    Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.

  • 26.
    Forsberg, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pekar, Gyula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Piotrowski, Arkadiusz
    Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80416 Gdansk, Poland..
    Absher, Devin
    HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA..
    Razzaghian, Hamid Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ambicka, Aleksandra
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Halaszka, Krzysztof
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Przewoznik, Marcin
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Kruczak, Anna
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Mandava, Geeta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pasupulati, Saichand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hacker, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Prakash, K. Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dasari, Ravi Chandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lau Börjesson, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Penagos-Tafurt, Nelly
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olofsson, Helena M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hallberg, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Skotnicki, Piotr
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Mitus, Jerzy
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Skokowski, Jaroslaw
    Med Univ Gdansk, Dept Surg Oncol, PL-80952 Gdansk, Poland.;Med Univ Gdansk, Dept Med Lab Diagnost, Bank Frozen Tissues & Genet Specimens, PL-80211 Gdansk, Poland..
    Jankowski, Michal
    Nicolaus Copernicus Univ, Ctr Oncol, Coll Med, Surg Oncol, PL-85796 Bydgoszcz, Poland..
    Srutek, Ewa
    Nicolaus Copernicus Univ, Ctr Oncol, Coll Med, Surg Oncol, PL-85796 Bydgoszcz, Poland..
    Zegarski, Wojciech
    Nicolaus Copernicus Univ, Ctr Oncol, Coll Med, Surg Oncol, PL-85796 Bydgoszcz, Poland..
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rys, Janusz
    Maria Sklodowska Curie Mem Inst Oncol, Krakow Branch, Ctr Oncol, PL-31115 Krakow, Poland..
    Tot, Tibor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer2015In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 10, p. 1521-1535Article in journal (Refereed)
    Abstract [en]

    Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

  • 27.
    Forsberg, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Razzaghian, Hamid R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Pakalapati, Geeta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Waite, Lindsay
    Thilbeault, Krista Stanton
    Ronowicz, Anna
    Wineinger, Nathan E
    Tiwari, Hemant K
    Boomsma, Dorret
    Westerman, Maxwell P
    Harris, Jennifer R
    Lyle, Robert
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Assimes, Themistocles L
    Iribarren, Carlos
    Strachan, Eric
    O'Hanlon, Terrance P
    Rider, Lisa G
    Miller, Frederick W
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Piotrowski, Arkadiusz
    Pedersen, Nancy L
    Absher, Devin
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Age-related somatic structural changes in the nuclear genome of human blood cells2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 2, p. 217-228Article in journal (Refereed)
    Abstract [en]

    Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

  • 28. Lawrie, Andrew S.
    et al.
    Pizzey, Arnold
    Trompeter, Sara
    Meiselman, Herbert
    Mohandas, Narla
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Westerman, Maxwell P.
    Procoagulant activity in patients with sickle cell trait2012In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 23, no 4, p. 268-270Article in journal (Refereed)
    Abstract [en]

    Patients with sickle cell trait (STr) are usually considered to be asymptomatic. However, complications, including hypercoagulability, increased risk of venous thromboembolism and the exertional exercise syndrome with rhabdomyolysis and sudden death, have been described. The exact cause of these adverse events is unclear. We have investigated two patients, a set of monozygotic twins with STr, to establish their procoagulant activity status as a potential indicator of thrombotic risk. In-vivo thrombin generation was assessed by the measurement of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT). D-dimer was used as a marker of fibrinolytic activity. The potential to generate thrombin was determined using an ex-vivo thrombin generation test (TGT). The impact of red blood cell (RBC)-derived microparticle shedding and RBC rheology were examined. TAT (>60 mu g/l) and F1+2 (948 pmol/l) were markedly elevated in patient 2 but within the normal reference range in patient 1 (TAT=2.5 mu g/l; F1+2=138 pmol/l). D-dimer levels (0.9 mg/l FEU) were similarly elevated in both patients. TGT peak thrombin and endogenous thrombin potential (ETP) were elevated to similar degrees in both patients. Flow cytometric analysis for RBC-derived microparticles showed that both patients had elevated levels on two occasions. RBC deformability, blood viscosity and RBC aggregation were normal and similar in both patients. The results demonstrated different coagulation activity in the patients with one patient in a prothrombotic state, suggesting that there may be two levels of hypercoagulability in STr. Measurement of such differences would allow for separation of high and low-risk patients from serious complications.

  • 29. Mantripragada, Kiran K
    et al.
    Diaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Patridge, Chris
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Chuzhanova, Nadia
    Kluwe, Lan
    Guha, Abhijit
    Mautner, Victor
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Upadhyaya, Meena
    Genome-wide high-resolution analysis of DNA copy number alterations in NF1-associated malignant peripheral nerve sheath tumors using 32K BAC array2009In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 48, no 10, p. 897-907Article in journal (Refereed)
    Abstract [en]

    Neurofibromatosis Type I (NF1) is an autosomal dominant disorder characterized by the development of both benign and malignant tumors. The lifetime risk for developing a malignant peripheral nerve sheath tumor (MPNST) in NF1 patients is approximately 10% with poor survival rates. To date, the molecular basis of MPNST development remains unclear. Here, we report the first genome-wide and high-resolution analysis of DNA copy number alterations in MPNST using the 32K bacterial artificial chromosome microarray on a series of 24 MPNSTs and three neurofibroma samples. In the benign neurofibromas, apart from loss of one copy of the NF1 gene and copy number polymorphisms, no other changes were found. The profiles of malignant samples, however, revealed specific loss of chromosomal regions including 1p35-33, 1p21, 9p21.3, 10q25, 11q22-23, 17q11, and 20p12.2 as well as gain of 1q25, 3p26, 3q13, 5p12, 5q11.2-q14, 5q21-23, 5q31-33, 6p23-p21, 6p12, 6q15, 6q23-q24, 7p22, 7p14-p13, 7q21, 7q36, 8q22-q24, 14q22, and 17q21-q25. Copy number gains were more frequent than deletions in the MPNST samples (62% vs. 38%). The genes resident within common regions of gain were NEDL1 (7p14), AP3B1 (5q14.1), and CUL1 (7q36.1) and these were identified in >63% MPNSTs. The most frequently deleted locus encompassed CDKN2A, CDKN2B, and MTAP genes on 9p21.3 (33% cases). These genes have previously been implicated in other cancer conditions and therefore, should be considered for their therapeutic, prognostic, and diagnostic relevance in NF1 tumorigenesis.

  • 30.
    Mantripragada, Kiran K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Piotrowski, Arek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Diaz De Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Grigelionis, Gintautas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ferner, R
    Griffiths, Sian
    Bolund, Lars
    Mautner, Victor
    Nordling, M
    Legius, E
    Vetrie, D
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Messiaen, L
    Upadhyaya, M
    Bruder, C E G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH2006In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 43, no 1, p. 28-38Article in journal (Refereed)
    Abstract [en]

    Background: Segmental duplications flanking the neurofibromatosis type 1 ( NF1) genelocus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report theconstruction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11,using a non- redundant approach for array design. The average resolution of analysis for the array is similar to 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1gene. Methods: We performed a comprehensive array- CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in26 cases, whereas 13 samples showed atypical deletion profiles. Results: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of thedeletion. The deletions identified by array- CGH were independently confirmed using multiplex ligation- dependent probe amplification. Bioinformatic analysis of the entire locus identified 33segmental duplications. Conclusions: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.

  • 31. Mikhail, Fady M.
    et al.
    Descartes, Maria
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bruder, Carl E. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carroll, Andrew J.
    A previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 encompassing the BCR gene2007In: American journal of medical genetics. Part A, ISSN 1552-4825, Vol. 143A, no 18, p. 2178-2184Article in journal (Refereed)
    Abstract [en]

    Susceptibility of the chromosome 22q11.2 region to rearrangements has been recognized on the basis of common clinical disorders such as the DiGeorge/velocardiofacial syndrome (DG/VCFs). Recent evidence has implicated low-copy repeats (LCRs); also known as segmental duplications; on 22q as mediators of nonallelic homologous recombination (NAHR) that result in rearrangements of 22q11.2. It has been shown that both deletion and duplication events can occur as a result of NAHR caused by unequal crossover of LCRs. Here we report on the clinical, cytogenetic and array CGH studies of a 15-year-old Hispanic boy with history of learning and behavior problems. We suggest that he represents a previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 just telomeric to the DG/VCFs typically deleted region and encompassing the BCR gene. Using a 32K BAC array CGH chip we were able to refine and precisely narrow the breakpoints of this microdeletion, which was estimated to be 1.55-1.92 Mb in size and to span approximately 20 genes. This microdeletion region is flanked by LCR clusters containing several modules with a very high degree of sequence homology (>95%), and therefore could play a causal role in its origin.

  • 32. Mikhail, Fady M.
    et al.
    Sathienkijkanchai, Achara
    Robin, Nathaniel H.
    Prucka, Sandra
    Biggerstaff, Julie Sanford
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bruder, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carroll, Andrew J.
    Overlapping phenotype of wolf-hirschhorn and beckwith-wiedemann syndromes in a girl with der(4)t(4; 1 1)(pter;pter)2007In: American Journal of Medical Genetics, Part A, ISSN 1552-4825, Vol. 143, no 15, p. 1760-1766Article in journal (Refereed)
    Abstract [en]

    We report on an 8-month-old girl with a novel unbalanced chromosomal rearrangement, consisting of a terminal deletion of 4p and a paternal duplication of terminal 11p. Each of these is associated with the well-known clinical phenotypes of Wolf-Hirschhorn syndrome (WHS) and Beckwith-Wiedemann syndrome (BWS), respectively. She presented for clinical evaluation of dysmorphic facial features, developmental delay, atrial septal defect (ASD), and left hydro-nephrosis. High-resolution cytogenetic analysis revealed a normal female karyotype, but subtelomeric fluorescence in situ hybridization (FISH) analysis revealed a der(4)t(4;11) (pter;pter). Both FISH and microarray CGH studies clearly demonstrated that the WHS critical regions 1 and 2 were deleted, and that the BWS imprinted domains (ID) 1 and 2 were duplicated on the der(4). Parental chromosome analysis revealed that the father carried a cryptic balanced t(4;11)(pter;pter). As expected, our patient manifests findings of both WHS (a growth retardation syndrome) and BWS (an overgrowth syndrome). We compare her unique phenotypic features with those that have been reported for both syndromes.

  • 33.
    Nord, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hartmann, Christian
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Piotrowski, Arkadiusz
    Bogdan, Adam
    Kloc, Wojciech
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    von Deimling, Andreas
    Bruder, Carl E. G.
    Southern Research Institute, Birmingham, AL, USA.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Ståhl, Teresita Díaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array2009In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 11, no 6, p. 803-818Article in journal (Refereed)
    Abstract [en]

    Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.

  • 34.
    Pekar, Gyula
    et al.
    Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun, Sweden.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lukacs, Agnes P
    Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun, Sweden.
    Forsberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Hellberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tot, Tibor
    Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun, Sweden.
    Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content2016In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 68, no 3, p. 411-421Article in journal (Refereed)
    Abstract [en]

    AIMS: To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 μg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability.

    METHODS AND RESULTS: We examined 57 breast surgical specimens with multifocal (46/57) and unifocal (11/57) cancers. Punch biopsies were obtained from tissue slices under multimodal radiological guidance, and the colour-coded sampling sites were identified in large-format histology slides. The study comprised 415 DNA isolations from tumour (n = 105) and normal (n = 283) tissue, including skin (n = 27) samples. A single 2-mm core from invasive tumour contained sufficient DNA in 91.4% (96/105) of cases, depending on tumour type (3.8-108.2 μg/sample), number and size of additional foci in multifocal cases (P = 0.001), tumour consistency, and degree of necrosis. Three biopsies obtained with a 4-mm device were required from normal breast tissue, at least 10 mm from the tumour. Cold ischaemia for up to 82 min did not influence the yield of DNA.

    CONCLUSIONS: Radiological disease mapping is useful for guiding optimal specimen slicing and for targeting breast lesions. A single 2-mm core from tumour and multiple 4-mm cores from normal breast tissue yield adequate DNA in the majority of samples.

  • 35. Piotrowski, Arkadiusz
    et al.
    Bruder, Carl E G
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Poplawski, Andrzej
    von Tell, Desiree
    Crasto, Chiquito
    Bogdan, Adam
    Bartoszewski, Rafal
    Bebok, Zsuzsa
    Krzyzanowski, Maciej
    Jankowski, Zbigniew
    Partridge, E Christopher
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Somatic mosaicism for copy number variation in differentiated human tissues2008In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 29, no 9, p. 1118-24Article in journal (Refereed)
    Abstract [en]

    Two major types of genetic variation are known: single nucleotide polymorphisms (SNPs), and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. We tested 34 tissue samples from three subjects and, having analyzed for each tissue < or =10(-6) of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82 to 176 kb, often encompassing known genes, potentially affecting gene function. Our results indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. The majority of described CNVs were previously shown to be polymorphic between unrelated subjects, suggesting that some CNVs previously reported as germline might represent somatic events, since in most studies of this kind, only one tissue is typically examined and analysis of parents for the studied subjects is not routinely performed. A considerable number of human phenotypes are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues to better address mosaicism in the studies of somatic disorders.

  • 36.
    Razzaghian, Hamid Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Forsberg, Lars Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Prakash, Kancherla Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Przerada, Szymon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Paprocka, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Zywicka, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Westerman, Maxwell P
    Pedersen, Nancy L
    O'Hanlon, Terrance P
    Rider, Lisa G
    Miller, Frederick W
    Srutek, Ewa
    Jankowski, Michal
    Zegarski, Wojciech
    Piotrowski, Arkadiusz
    Absher, Devin
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Post-Zygotic and Inter-Individual Structural Genetic Variation in a Presumptive Enhancer Element of the Locus between the IL10Rβ and IFNAR1 Genes2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e67752-Article in journal (Refereed)
    Abstract [en]

    Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in similar to 24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10R beta, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.

  • 37.
    Ronowicz, Anna
    et al.
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Janaszak-Jasiecka, Anna
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Skokowski, Jaroslaw
    Med Univ Gdansk, Cent Bank Tissues & Genet Specimens, PL-80416 Gdansk, Poland.;Med Univ Gdansk, Dept Surg Oncol, PL-80416 Gdansk, Poland..
    Madanecki, Piotr
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Bartoszewski, Rafal
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Balut, Magdalena
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Seroczynska, Barbara
    Med Univ Gdansk, Cent Bank Tissues & Genet Specimens, PL-80416 Gdansk, Poland..
    Kochan, Kinga
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Bogdan, Adam
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Butkus, Malgorzata
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Peksa, Rafal
    Med Univ Gdansk, Dept Pathomorphol, PL-80416 Gdansk, Poland..
    Ratajska, Magdalena
    Med Univ Gdansk, Dept Biol & Genet, PL-80416 Gdansk, Poland..
    Kuzniacka, Alina
    Med Univ Gdansk, Dept Biol & Genet, PL-80416 Gdansk, Poland..
    Wasag, Bartosz
    Med Univ Gdansk, Dept Biol & Genet, PL-80416 Gdansk, Poland..
    Gucwa, Magdalena
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Krzyzanowski, Maciej
    Med Univ Gdansk, Dept Forens Med, PL-80416 Gdansk, Poland..
    Jaskiewicz, Janusz
    Med Univ Gdansk, Dept Surg Oncol, PL-80416 Gdansk, Poland..
    Jankowski, Zbigniew
    Med Univ Gdansk, Dept Forens Med, PL-80416 Gdansk, Poland..
    Forsberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ochocka, J. Renata
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Limon, Janusz
    Med Univ Gdansk, Dept Biol & Genet, PL-80416 Gdansk, Poland..
    Crowley, Michael R.
    Univ Alabama Birmingham, Heflin Ctr Genom Sci, Birmingham, AL USA..
    Buckley, Patrick G.
    Beaumont Hosp, Mol Pathol Lab, Dublin 9, Ireland..
    Messiaen, Ludwine
    Univ Alabama Birmingham, Dept Genet, Med Genom Lab, Birmingham, AL USA..
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Piotrowski, Arkadiusz
    Med Univ Gdansk, Fac Pharm, PL-80416 Gdansk, Poland..
    Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 11, p. 1088-1099Article in journal (Refereed)
    Abstract [en]

    Somatic mosaicism for DNA copy-number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array-based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC-CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.

  • 38. Sandgren, Johanna
    et al.
    Andersson, A
    Rada-Iglesias, A
    Enroth, S
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dumanski, Jan
    Komorowski, J
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wadelius, Claes
    Integrative epigenomic and genomic analysis of malignant pheochromocytoma.2010In: Experimental and Molecular Medicine, ISSN 1226-3613, E-ISSN 2092-6413, Vol. 42, p. 484-502Article in journal (Refereed)
  • 39.
    Sandgren, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Diaz de Ståhl, T
    Andersson, R
    Menzel, U
    Piotrowski, A
    Nord, H
    Bäckdahl, M
    Kiss, N
    Braukhoff, M
    Komorowski, J
    Dralle, H
    Hessman, O
    Larsson, C
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bruder, C
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array-CGH analysis.2010In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 17, p. 561-579Article in journal (Refereed)
  • 40. Score, J.
    et al.
    Chase, A.
    Forsberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Feng, L.
    Waghorn, K.
    Jones, A. V.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Linch, D. C.
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gale, R. E.
    Cross, N. C. P.
    Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 7, p. 1600-1602Article in journal (Refereed)
  • 41. Thompson, Deborah J
    et al.
    Genovese, Giulio
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ulirsch, Jacob C
    Wright, Daniel J
    Terao, Chikashi
    Davidsson, Olafur B
    Day, Felix R
    Sulem, Patrick
    Jiang, Yunxuan
    Danielsson, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dennis, Joe
    Dunlop, Malcolm G
    Easton, Douglas F
    Fisher, Victoria A
    Zink, Florian
    Houlston, Richard S
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kar, Siddhartha
    Kerrison, Nicola D
    Kinnersley, Ben
    Kristjansson, Ragnar P
    Law, Philip J
    Li, Rong
    Loveday, Chey
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    McCarroll, Steven A
    Murakami, Yoshinori
    Murray, Anna
    Olszewski, Pawel
    Rychlicka-Buniowska, Edyta
    Scott, Robert A
    Thorsteinsdottir, Unnur
    Tomlinson, Ian
    Moghadam, Behrooz Torabi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Turnbull, Clare
    Wareham, Nicholas J
    Gudbjartsson, Daniel F
    Kamatani, Yoichiro
    Hoffmann, Eva R
    Jackson, Steve P
    Stefansson, Kari
    Auton, Adam
    Ong, Ken K
    Machiela, Mitchell J
    Loh, Po-Ru
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Chanock, Stephen J
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Perry, John R B
    Genetic predisposition to mosaic Y chromosome loss in blood.2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687Article in journal (Refereed)
    Abstract [en]

    Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

  • 42.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Edeby, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ellis, P.
    Langford, C.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation2007In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 118, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Chromosomal imbalances are the major cause of mental retardation (MR). Many of these imbalances are caused by submicroscopic deletions or duplications not detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array-CGH) is considered to be superior for the investigation of chromosomal aberrations in children with MR, and has been demonstrated to improve the diagnostic detection rate of these small chromosomal abnormalities. In this study we used 1 Mb genome-wide array-CGH to screen 48 children with MR and congenital malformations for submicroscopic chromosomal imbalances, where the underlying cause was unknown. All children were clinically investigated and subtelomere FISH analysis had been performed in all cases. Suspected microdeletion syndromes such as deletion 22q11.2, Williams-Beuren and Angelman syndromes were excluded before array-CGH analysis was performed. We identified de novo interstitial chromosomal imbalances in two patients (4%), and an interstitial deletion inherited from an affected mother in one patient (2%). In another two of the children (4%), suspected imbalances were detected but were also found in one of the non-affected parents. The yield of identified de novo alterations detected in this study is somewhat less than previously described, and might reflect the importance of which selection criterion of patients to be used before array-CGH analysis is performed. However, array-CGH proved to be a high-quality and reliable tool for genome-wide screening of MR patients of unknown etiology.

1 - 42 of 42
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