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Publications (10 of 42) Show all publications
Thompson, D. J., Genovese, G., Halvardson, J., Ulirsch, J. C., Wright, D. J., Terao, C., . . . Perry, J. R. (2019). Genetic predisposition to mosaic Y chromosome loss in blood. Nature, 575, 652-657
Open this publication in new window or tab >>Genetic predisposition to mosaic Y chromosome loss in blood
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2019 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 575, p. 652-657Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397756 (URN)10.1038/s41586-019-1765-3 (DOI)000500036800057 ()31748747 (PubMedID)
Funder
EU, European Research Council, 679744
Note

Lars Forsberg and John Perry contributed equally to this work

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-01-13Bibliographically approved
Danielsson, M., Halvardson, J., Davies, H., Moghadam, B. T., Mattisson, J., Rychlicka-Buniowska, E., . . . Forsberg, L. A. (2019). Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals. European Journal of Human Genetics
Open this publication in new window or tab >>Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed) Epub ahead of print
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.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397754 (URN)10.1038/s41431-019-0533-z (DOI)31654039 (PubMedID)
Note

These authors contributed equally: Jan P. Dumanski, Lars A. Forsberg

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2019-11-25Bibliographically approved
Forsberg, L. A., Halvardson, J., Rychlicka-Buniowska, E., Danielsson, M., Moghadam, B. T., Mattisson, J., . . . Dumanski, J. P. (2019). Mosaic loss of chromosome Y in leukocytes matters [Letter to the editor]. Nature Genetics, 51(1), 4-7
Open this publication in new window or tab >>Mosaic loss of chromosome Y in leukocytes matters
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 4-7Article in journal, Letter (Other academic) Published
National Category
Medical Genetics Genetics
Identifiers
urn:nbn:se:uu:diva-373366 (URN)10.1038/s41588-018-0267-9 (DOI)000454108800004 ()30374072 (PubMedID)
Funder
EU, European Research CouncilSwedish Research Council
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Chase, A., Pellagatti, A., Singh, S., Score, J., Tapper, W. J., Lin, F., . . . Cross, N. C. P. (2019). PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia. Leukemia, 33(5), 1184-1194
Open this publication in new window or tab >>PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 5, p. 1184-1194Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-383506 (URN)10.1038/s41375-018-0340-5 (DOI)000466360100011 ()30573780 (PubMedID)
Available from: 2019-05-17 Created: 2019-05-17 Last updated: 2019-05-17Bibliographically approved
Dumanski, J. P., Rasi, C., Björklund, P., Davies, H., Ali, A. S., Grönberg, M., . . . Tiensuu Janson, E. (2017). A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocrine-Related Cancer, 24(8), 427-443
Open this publication in new window or tab >>A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
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2017 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 8, p. 427-443Article in journal (Refereed) Published
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.

Keywords
DNA excision-repair pathway, cancer predisposition, familial cancer, oxidative stress, small intestinal carcinoid
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-328686 (URN)10.1530/ERC-17-0196 (DOI)000406493000011 ()28634180 (PubMedID)
Available from: 2017-08-29 Created: 2017-08-29 Last updated: 2019-02-07Bibliographically approved
Dumanski, J. P., Sundström, J. & Forsberg, L. A. (2017). Loss of Chromosome Y in Leukocytes and Major Cardiovascular Events. Circulation: Cardiovascular Genetics, 10(4)
Open this publication in new window or tab >>Loss of Chromosome Y in Leukocytes and Major Cardiovascular Events
2017 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 4Article in journal, Editorial material (Other academic) Published
National Category
Medical Genetics Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-328138 (URN)10.1161/CIRCGENETICS.117.001820 (DOI)000407206100014 ()28768755 (PubMedID)
Funder
EU, European Research Council, ERC Starting GrantStiftelsen Olle Engkvist ByggmästareSwedish Cancer SocietySwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-08-18 Created: 2017-08-18 Last updated: 2019-02-22Bibliographically approved
Forsberg, L. A., Gisselsson, D. & Dumanski, J. P. (2017). Mosaicism in health and disease — clones picking up speed. Nature reviews genetics, 18(2), 128-142
Open this publication in new window or tab >>Mosaicism in health and disease — clones picking up speed
2017 (English)In: Nature reviews genetics, ISSN 1471-0056, E-ISSN 1471-0064, Vol. 18, no 2, p. 128-142Article, review/survey (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-310195 (URN)10.1038/nrg.2016.145 (DOI)000392906800010 ()27941868 (PubMedID)
Funder
Stiftelsen Olle Engkvist ByggmästareSwedish Cancer SocietySwedish Research CouncilSwedish Heart Lung FoundationTorsten Söderbergs stiftelseScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Childhood Cancer FoundationThe Crafoord Foundation
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2019-01-25Bibliographically approved
Pekar, G., Davies, H., Lukacs, A. P., Forsberg, L., Hellberg, D., Dumanski, J. & Tot, T. (2016). Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content. Histopathology, 68(3), 411-421
Open this publication in new window or tab >>Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content
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2016 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 68, no 3, p. 411-421Article in journal (Refereed) Published
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.

Keywords
biobanking; breast cancer; DNA quality and quantity; heterogeneity; multifocality
National Category
Medical and Health Sciences Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-271418 (URN)10.1111/his.12758 (DOI)000367819400011 ()26083274 (PubMedID)
Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2018-01-10Bibliographically approved
Dumanski, J. P., Lambert, J.-C., Rasi, C., Giedraitis, V., Davies, H., Grenier-Boley, B., . . . Forsberg, L. A. (2016). Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease. American Journal of Human Genetics, 98(6), 1208-1219
Open this publication in new window or tab >>Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
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2016 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 98, no 6, p. 1208-1219Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-299047 (URN)10.1016/j.ajhg.2016.05.014 (DOI)000377286000014 ()27231129 (PubMedID)
External cooperation:
Funder
Stiftelsen Olle Engkvist ByggmästareEU, European Research CouncilSwedish Cancer SocietySwedish Research CouncilSwedish Heart Lung FoundationTorsten Söderbergs stiftelseWellcome trust, WT098017 WT064890 WT090532
Available from: 2016-07-13 Created: 2016-07-13 Last updated: 2018-01-10Bibliographically approved
Ronowicz, A., Janaszak-Jasiecka, A., Skokowski, J., Madanecki, P., Bartoszewski, R., Balut, M., . . . Piotrowski, A. (2015). Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients. Human Mutation, 36(11), 1088-1099
Open this publication in new window or tab >>Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 11, p. 1088-1099Article in journal (Refereed) Published
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.

Keywords
breast cancer, genome stability, somatic mosaicism, rearrangement, CNA, CNV, driver mutations
National Category
Genetics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-266686 (URN)10.1002/humu.22845 (DOI)000362991400012 ()26219265 (PubMedID)
Available from: 2015-11-12 Created: 2015-11-10 Last updated: 2017-12-01Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-1489-1452

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