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5 results on '"Vuorela M"'

1. RAD51B in Familial Breast Cancer.

Author

Pelttari LM, Khan S, Vuorela M, Kiiski JI, Vilske S, Nevanlinna V, Ranta S, Schleutker J, Winqvist R, Kallioniemi A, Dörk T, Bogdanova NV, Figueroa J, Pharoah PD, Schmidt MK, Dunning AM, García-Closas M, Bolla MK, Dennis J, Michailidou K, Wang Q, Hopper JL, Southey MC, Rosenberg EH, Fasching PA, Beckmann MW, Peto J, Dos-Santos-Silva I, Sawyer EJ, Tomlinson I, Burwinkel B, Surowy H, Guénel P, Truong T, Bojesen SE, Nordestgaard BG, Benitez J, González-Neira A, Neuhausen SL, Anton-Culver H, Brenner H, Arndt V, Meindl A, Schmutzler RK, Brauch H, Brüning T, Lindblom A, Margolin S, Mannermaa A, Hartikainen JM, Chenevix-Trench G, Van Dyck L, Janssen H, Chang-Claude J, Rudolph A, Radice P, Peterlongo P, Hallberg E, Olson JE, Giles GG, Milne RL, Haiman CA, Schumacher F, Simard J, Dumont M, Kristensen V, Borresen-Dale AL, Zheng W, Beeghly-Fadiel A, Grip M, Andrulis IL, Glendon G, Devilee P, Seynaeve C, Hooning MJ, Collée M, Cox A, Cross SS, Shah M, Luben RN, Hamann U, Torres D, Jakubowska A, Lubinski J, Couch FJ, Yannoukakos D, Orr N, Swerdlow A, Darabi H, Li J, Czene K, Hall P, Easton DF, Mattson J, Blomqvist C, Aittomäki K, and Nevanlinna H

Subjects
Breast Neoplasms etiology, DNA-Binding Proteins physiology, Female, Finland, Genetic Predisposition to Disease genetics, Genotyping Techniques, Haplotypes genetics, Heterozygote, Humans, Male, Middle Aged, Mutation, Missense, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Polymorphism, Single Nucleotide genetics
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Published
2016
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2. Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility.

Author

Vuorela M, Pylkäs K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt Wäppling A, Haanpää M, Puistola U, Rosengren A, Anttila M, Kosma VM, Mannermaa A, and Winqvist R

Subjects
Adolescent, Adult, Aged, Alleles, Base Sequence, Child, Child, Preschool, Female, Germ-Line Mutation, Humans, Middle Aged, Pedigree, Young Adult, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics
Abstract

RAD51C, a RAD51 paralogue involved in homologous recombination, is a recently established Fanconi anemia and breast cancer predisposing factor. In the initial report, RAD51C mutations were shown to confer a high risk for both breast and ovarian tumors, but most of the replication studies published so far have failed to identify any additional susceptibility alleles. Here, we report a full mutation screening of the RAD51C gene in 147 Finnish familial breast cancer cases and in 232 unselected ovarian cancer cases originating from Finland and Sweden. In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants. Whereas, none of the studied common SNPs associated with breast cancer susceptibility, mutation analysis revealed two clearly pathogenic alterations. RAD51C c.-13_14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low. Independent identification of the very recently reported RAD51C c.774delT mutation in yet another patient originating from Sweden suggests that it might be a recurrent mutation in that population and should be studied further. The reliable estimation of the clinical implications of carrying a defective RAD51C allele still requires the identification of additional mutation positive families.

Published
2011
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3. Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families.

Author

Vuorela M, Pylkäs K, and Winqvist R

Subjects
Adult, Aged, Aged, 80 and over, Base Sequence, DNA Mutational Analysis, DNA Primers genetics, DNA, Neoplasm genetics, Female, Finland, Genetic Predisposition to Disease, Genetic Testing, Heterozygote, Humans, Middle Aged, Ubiquitin-Protein Ligases, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Ligases genetics, Ubiquitin-Conjugating Enzymes genetics
Abstract

Background: Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, RNF8, UBC13 and MMS2 were considered plausible candidate genes for susceptibility to breast cancer., Methods: The entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing., Results: Mutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to associate with breast cancer susceptibility., Conclusions: The present data suggest that mutations in RNF8, UBC13 and MMS2 genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.

Published
2011
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4. Role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes and rare copy number variants in hereditary predisposition to breast cancer

Author

Vuorela, M. (Mikko), Winqvist, R. (Robert), and Pylkäs, K. (Katri)

Subjects
DNA copy number variations, DNA-kopiomäärän vaihtelut, estrogeenit, perinnöllisyystiede, tumor suppressor protein p53, ubiquitin-conjugating enzymes, DNA-mutaatioanalyysi, rinnan kasvaimet, n sitojaproteiinit [DNA], ituradan mutaatio, Fanconi anemia, DNA-binding proteins, DNA mutational analysis, breast neoplasms, genetics, ubikitiini-konjugaatioentsyymit, germ-line mutation, Fanconin anemia, kasvainsalpaajaproteiini p53, estrogens
Abstract

Mutations in the currently known breast cancer susceptibility genes account for only 25–30% of all familial cases. Novel susceptibility genes can be identified by several methods, including candidate gene re-sequencing and genome-wide microarrays. We have applied microarrays for the detection of a new genomic variation class, copy number variants (CNVs), which potentially could disrupt genes in multiple pathways related to breast cancer susceptibility. The aim of the current study was to evaluate the role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes in breast cancer susceptibility as well as to study if rare CNVs are associated with the predisposition to this disease. The analysis of 123 familial breast cancer cases revealed altogether nine different changes in the RNF8 and UBC13 candidate genes. However, none of the observed alterations were considered pathogenic. No alterations were observed in MMS2. The obtained results suggest that breast cancer predisposing alterations in RNF8, UBC13 and MMS2 are rare, or even absent. The RAD51C mutation screening of 147 familial breast cancer cases and 232 unselected ovarian cancer cases revealed two deleterious mutations: c.-13_14del27 was observed in a breast cancer case with familial history of ovarian cancer and c.774delT in an ovarian cancer case. Both mutations were absent in the control cohort. The results of the study support the hypothesis that rare variants of RAD51C predispose predominantly to ovarian cancer. A genome-wide scan of CNVs was performed for 103 familial breast cancer cases and 128 controls. The biological networks of the genes disrupted by CNVs were different between the two groups. In familial breast cancer cases, the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity (P=0.0211). Biological network analysis showed that the disrupted genes were closely related to estrogen signaling and TP53-centered tumor suppressor network, and this result was confirmed by the analysis of an independent young breast cancer cohort of 75 cases. These results suggest that rare CNVs represent an alternative source of genetic variation contributing to hereditary risk for breast cancer. Tiivistelmä Tunnetut rintasyöpäalttiusgeenien mutaatiot selittävät vain 25–30 prosenttia kaikista perinnöllisistä rintasyöpätapauksista. Uusia alttiusgeenejä voidaan tunnistaa useilla eri menetelmillä, kuten kandidaattigeenien mutaatiokartoituksella ja genomin-laajuisilla mikrosirutekniikoilla. Tässä tutkimuksessa sovelsimme mikrosirutekniikkaa uuden geneettisen variaatioluokan, kopiolukuvariaation (CNV), tutkimiseen. CNV:t voivat vaurioittaa lukuisia rintasyöpäalttiuteen liittyviä biokemiallisia reittejä. Tämän tutkimuksen tarkoitus oli arvioida RNF8-, UBC13-, MMS2- ja RAD51C -DNA- vauriovastegeenien sekä harvinaisten CNV:iden yhteyttä rintasyöpä-alttiuteen. 123 familiaalisen rintasyöpätapauksen analyysissä löytyi yhteensä yhdeksän muutosta RNF8- ja UBC13-geeneistä, joista yksikään ei osoittautunut patogeeniseksi. MMS2-geenissä ei havaittu muutoksia. Tulosten perusteella rintasyövälle altistavat muutokset RNF8-, UBC13- ja MMS2- geeneissä ovat joko erittäin harvinaisia tai niitä ei esiinny lainkaan. RAD51C-geenin mutaatiokartoitus 147 familiaalisesta rintasyöpätapauksesta sekä 232 valikoimattomasta munasarjasyöpätapauksesta paljasti kaksi haitallista mutaatiota. c.-13_14del27 havaittiin rintasyöpäpotilaalla, jonka suvussa esiintyi munasarjasyöpää, ja c.774delT todettiin munasarjasyöpäpotilaalta. Kumpaakaan mutaatiota ei havaittu verrokkiaineistossa. Tulokset vahvistavat hypoteesia RAD51C-geenin harvinaisten varianttien yhteydestä pääasiassa munasarjasyöpäriskiin. CNV:iden genomin-laajuinen skannaaminen suoritettiin 103 familiaaliselle rintasyöpätapaukselle ja 128 verrokille. CNV:iden häiritsemien geenien muodostamat biologiset verkostot olivat erilaiset näiden kahden ryhmän välillä. Familiaalisilla rintasyöpätapauksilla havaitut CNV:t vaikuttivat geeneihin, jotka olivat voimakkaasti korostuneita genomin eheyttä ylläpitävissä tehtävissä (P=0.0211). Biologisten verkostojen analyysi paljasti, että CNV:iden vahingoittamat geenit liittyivät läheisesti estrogeenisignalointiin sekä TP53-tuumorisupressoriverkostoon, ja tämä tulos vahvistettiin analysoimalla riippumatonta nuorista rintasyöpäpotilaista koostuvaa kohorttia (N=75). Tutkimuksen tulosten mukaan harvinaiset CNV:t ovat vaihtoehtoinen geneettisen variaation lähde perinnölliseen rintasyöpäalttiuteen.

Published
2013

5. RAD51B in Familial Breast Cancer

Author

kConFab, Jonine Figueroa, Elinor J. Sawyer, Manjeet K. Bolla, Carl Blomqvist, Jaana M. Hartikainen, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Fredrick Schumacher, Vessela N. Kristensen, Graham G. Giles, Isabel dos-Santos-Silva, Kamila Czene, Douglas F. Easton, Qin Wang, Javier Benitez, Janet E. Olson, Georgia Chenevix-Trench, John L. Hopper, Alicia Beeghly-Fadiel, Hoda Anton-Culver, Paolo Radice, Aocs Investigators, Nick Orr, Jacques Simard, Mervi Grip, Salla Ranta, Fergus J. Couch, Marjanka K. Schmidt, Kristiina Aittomäki, Caroline Seynaeve, Ute Hamann, Johanna Schleutker, Hilde Janssen, Robert Luben, Anna González-Neira, Peter A. Fasching, Pascal Guénel, Anja Rudolph, Arto Mannermaa, Melissa C. Southey, Ian Tomlinson, Thérèse Truong, Alison M. Dunning, Margriet Collée, Robert Winqvist, Johanna Mattson, Mikko Vuorela, Sara Vilske, Anne Lise Børresen-Dale, Johanna I. Kiiski, Paolo Peterlongo, Anna Jakubowska, Paul D.P. Pharoah, Alfons Meindl, Anthony J. Swerdlow, Roger L. Milne, Hermann Brenner, Joe Dennis, Montserrat Garcia-Closas, Thomas Brüning, Christopher A. Haiman, Martine Dumont, Wei Zheng, Per Hall, Gord Glendon, Jingmei Li, Laurien Van Dyck, Susan L. Neuhausen, Simon S. Cross, Irene L. Andrulis, Peter Devilee, Annika Lindblom, Emily Hallberg, Diana Torres, Sofia Khan, Kyriaki Michailidou, Rita K. Schmutzler, Julian Peto, Harald Surowy, Børge G. Nordestgaard, Barbara Burwinkel, Natalia Bogdanova, Drakoulis Yannoukakos, Heli Nevanlinna, Jan Lubinski, Liisa M. Pelttari, Efraim H. Rosenberg, Hiltrud Brauch, Thilo Dörk, Angela Cox, Viivi Nevanlinna, Maartje J. Hooning, Volker Arndt, Anne Kallioniemi, Stig E. Bojesen, Jenny Chang-Claude, Hatef Darabi, Obstetrics & Gynecology, Clinical Genetics, Gastroenterology & Hepatology, Medical Oncology, Brusgaard, Klaus, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Thierry, B, Zeps, N, Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Heredity, XRCC2, Genotyping Techniques, lcsh:Medicine, Genome-wide association study, 14Q24.1 RAD51L1, VARIANTS, Geographical Locations, 3123 Gynaecology and paediatrics, Cancer screening, Breast Tumors, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, Ethnicities, lcsh:Science, Finland, Genetics, RISK, education.field_of_study, Multidisciplinary, GERMLINE MUTATIONS, Genomics, Middle Aged, 3. Good health, Ovarian Cancer, Europe, DNA-Binding Proteins, Genetic Mapping, Male breast cancer, Female, Cancer Screening, Research Article, medicine.medical_specialty, Heterozygote, General Science & Technology, Population, 3122 Cancers, Mutation, Missense, Single-nucleotide polymorphism, Variant Genotypes, Breast Neoplasms, Genome Complexity, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Breast Cancer, medicine, Cancer Detection and Diagnosis, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Evolutionary Biology, Population Biology, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Odds ratio, medicine.disease, ta3122, GENE, Introns, 030104 developmental biology, Haplotypes, FANCONI-ANEMIA, People and Places, lcsh:Q, Population Groupings, business, Ovarian cancer, Gynecological Tumors, Population Genetics, Finns
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. ispartof: PLoS One vol:11 issue:5 ispartof: location:United States status: published

Published
2016

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