uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Rasi, Chiara
Publications (10 of 10) Show all publications
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
Show others...
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
Show others...
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
Show others...
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., 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
Show others...
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
Score, J., Chase, A., Forsberg, L., Feng, L., Waghorn, K., Jones, A. V., . . . Cross, N. C. (2015). Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals [Letter to the editor]. Leukemia, 29(7), 1600-1602
Open this publication in new window or tab >>Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals
Show others...
2015 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 7, p. 1600-1602Article in journal, Letter (Refereed) Published
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:uu:diva-261061 (URN)10.1038/leu.2015.13 (DOI)000357623100020 ()25627638 (PubMedID)
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04Bibliographically approved
Dumanski, J. P., Rasi, C., Lönn, M., Davies, H., Ingelsson, M., Giedraitis, V., . . . Forsberg, L. A. (2015). Mutagenesis: smoking is associated with mosaic loss of chromosome Y. Science, 347(6217), 81-83
Open this publication in new window or tab >>Mutagenesis: smoking is associated with mosaic loss of chromosome Y
Show others...
2015 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6217, p. 81-83Article in journal (Refereed) Published
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.

National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-239522 (URN)10.1126/science.1262092 (DOI)000347102300053 ()25477213 (PubMedID)
External cooperation:
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
Chase, A., Leung, W., Tapper, W., Jones, A. V., Knoops, L., Rasi, C., . . . Cross, N. C. (2015). Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus. Leukemia, 29(10), 2069-2074
Open this publication in new window or tab >>Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus
Show others...
2015 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 10, p. 2069-2074Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-265835 (URN)10.1038/leu.2015.130 (DOI)000362507600013 ()26114957 (PubMedID)
External cooperation:
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-01-10Bibliographically approved
Forsberg, L. A., Rasi, C., Pekar, G., Davies, H., Piotrowski, A., Absher, D., . . . Dumanski, J. P. (2015). Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer. Genome Research, 25(10), 1521-1535
Open this publication in new window or tab >>Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
Show others...
2015 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 10, p. 1521-1535Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-265683 (URN)10.1101/gr.187823.114 (DOI)000362157400016 ()26430163 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Heart Lung FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2015-11-04 Created: 2015-11-02 Last updated: 2018-02-28Bibliographically approved
Forsberg, L. A., Rasi, C., Malmqvist, N., Davies, H., Pasupulati, S., Pakalapati, G., . . . Dumanski, J. P. (2014). Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer [Letter to the editor]. Nature Genetics, 46(6), 624-628
Open this publication in new window or tab >>Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
Show others...
2014 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 6, p. 624-628Article in journal, Letter (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-228467 (URN)10.1038/ng.2966 (DOI)000336870700021 ()
Available from: 2014-07-15 Created: 2014-07-15 Last updated: 2018-01-11Bibliographically approved
Forsberg, L. A., Rasi, C., Razzaghian, H. R., Pakalapati, G., Waite, L., Thilbeault, K. S., . . . Dumanski, J. P. (2012). Age-related somatic structural changes in the nuclear genome of human blood cells. American Journal of Human Genetics, 90(2), 217-228
Open this publication in new window or tab >>Age-related somatic structural changes in the nuclear genome of human blood cells
Show others...
2012 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 2, p. 217-228Article in journal (Refereed) Published
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.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-170952 (URN)10.1016/j.ajhg.2011.12.009 (DOI)000300742200003 ()22305530 (PubMedID)
External cooperation:
Funder
Swedish Research Council, 80576801;70374401Swedish Cancer Society
Available from: 2012-03-14 Created: 2012-03-14 Last updated: 2018-01-12Bibliographically approved
Organisations

Search in DiVA

Show all publications