Journal ArticleDOI
Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene
Alfons Meindl,Heide Hellebrand,Constanze Wiek,Verena Erven,Barbara Wappenschmidt,Dieter Niederacher,Marcel Freund,Peter Lichtner,Linda Hartmann,Heiner Schaal,Juliane Ramser,Ellen Honisch,Christian Kubisch,Hans Erich Wichmann,Karin Kast,Helmut Deissler,Christoph Engel,Bertram Müller-Myhsok,Kornelia Neveling,Marion Kiechle,Christopher G. Mathew,Detlev Schindler,Rita K. Schmutzler,Helmut Hanenberg,Helmut Hanenberg +24 more
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TLDR
In index cases from 1,100 German families with gynecological malignancies, the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog is provided and support the 'common disease, rare allele' hypothesis.Abstract:
Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.read more
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Therapeutic Approaches for Women Predisposed to Breast Cancer
TL;DR: Preclinical and early clinical research suggests that specific classes of chemotherapy may be more effective in mutation carriers, and PARP inhibitors represent a novel therapeutic strategy that exploits the weaknesses of BRCA1/2-associated malignancies.
Journal ArticleDOI
RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study.
Florence Le Calvez-Kelm,Javier Oliver,Francesca Damiola,Nathalie Forey,Nivonirina Robinot,Geoffroy Durand,Catherine Voegele,Maxime Vallée,Graham Byrnes,John L. Hopper,Melissa C. Southey,Irene L. Andrulis,Esther M. John,Esther M. John,Sean V. Tavtigian,Fabienne Lesueur +15 more
TL;DR: The data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.
Journal ArticleDOI
Genetic testing and personalized ovarian cancer screening: a survey of public attitudes
Susanne F. Meisel,Belinda Rahman,Lucy Side,Lindsay Fraser,Sue Gessler,Anne Lanceley,Jane Wardle +6 more
TL;DR: Assessment of attitudes to risk-stratified ovarian cancer screening based on prior genetic risk assessment gives confidence in taking forward research on integration of novel genomic technologies into mainstream healthcare.
Journal ArticleDOI
Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.
Alexandra V. Stavropoulou,Florentia Fostira,Maroulio Pertesi,Marianthi Tsitlaidou,Gerassimos E. Voutsinas,Olga Triantafyllidou,Aristotelis Bamias,Meletios A. Dimopoulos,Eleni Timotheadou,Dimitrios Pectasides,Christos Christodoulou,G. Klouvas,Christos Papadimitriou,Thomas Makatsoris,George Pentheroudakis,Gerasimos Aravantinos,Vassilis Karydakis,Drakoulis Yannoukakos,George Fountzilas,Irene Konstantopoulou +19 more
TL;DR: The prevalence of BRCA1 mutations was determined in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases to determine the prevalence of mutations in the rest of the BRCa1 gene, in the B RCA2 gene, and other novel predisposing genes for breast and ovarian cancer.
Journal ArticleDOI
Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma
Barbara Rivera,Massimo Di Iorio,Jessica Frankum,Javad Nadaf,Somayyeh Fahiminiya,Suzanna L. Arcand,David L. Burk,Damien Grapton,Eva Tomiak,Valerie Hastings,Nancy Hamel,Rabea Wagener,Olga Aleynikova,Sylvie Giroux,Fadi F. Hamdan,Alexandre Dionne-Laporte,George Zogopoulos,George Zogopoulos,François Rousseau,Albert M. Berghuis,Diane Provencher,Guy A. Rouleau,Jacques L. Michaud,Anne-Marie Mes-Masson,Jacek Majewski,Susanne Bens,Reiner Siebert,Steven A. Narod,Steven A. Narod,Mohammad R. Akbari,Mohammad R. Akbari,Christopher J. Lord,Patricia N. Tonin,Patricia N. Tonin,Alexandre Orthwein,William D. Foulkes +35 more
TL;DR: Using deep sequencing and case-control genotyping studies, this study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD 51D variants.
References
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Journal ArticleDOI
Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
TL;DR: Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset, and risks appear to be increasing with time.
Journal ArticleDOI
Biallelic Inactivation of BRCA2 in Fanconi Anemia
Niall G. Howlett,Toshiyasu Taniguchi,Susan B. Olson,Barbara Cox,Quinten Waisfisz,Christine E. M. de Die-Smulders,Nicole Persky,Markus Grompe,Hans Joenje,Gerard Pals,Hideyuki Ikeda,Edward A. Fox,Alan D. D'Andrea +12 more
TL;DR: It is shown that cell lines derived from FA-B and FA-D1 patients have biallelic mutations in BRCA2 and express truncated BRC a2 proteins, which may result in cancer risks similar to those observed in families withBRCA1 or BRCa2 mutations.
Journal ArticleDOI
Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene
Siân Jones,Siân Jones,Ralph H. Hruban,Mihoko Kamiyama,Michael Borges,Xiaosong Zhang,Xiaosong Zhang,D. Williams Parsons,D. Williams Parsons,Jimmy Lin,Jimmy Lin,Emily Palmisano,Kieran Brune,Elizabeth M. Jaffee,Christine A. Iacobuzio-Donahue,Anirban Maitra,Giovanni Parmigiani,Scott E. Kern,Victor E. Velculescu,Kenneth W. Kinzler,Bert Vogelstein,Bert Vogelstein,James R. Eshleman,Michael Goggins,Alison P. Klein +24 more
TL;DR: Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, a germline, truncating mutation in PALB2 was identified that appeared responsible for this patient's predisposition to the disease.
Journal ArticleDOI
Multifactorial Analysis of Differences Between Sporadic Breast Cancers and Cancers Involving BRCA1 and BRCA2 Mutations
Sunil R. Lakhani,Jocelyne Jacquemier,John P. Sloane,Barry A. Gusterson,Thomas J. Anderson,Marc J. van de Vijver,Linda M. Farid,Deon J. Venter,A C Antoniou,Amy Storfer-Isser,Elizabeth Smyth,C. Michael Steel,Neva E. Haites,Rodney J. Scott,David E. Goldgar,Susan L. Neuhausen,Peter A. Daly,Wilma Ormiston,Ross McManus,Siegfried Scherneck,Bruce A.J. Ponder,Debbie Ford,Julian Peto,Dominique Stoppa-Lyonnet,Yves-Jean Bignon,J. P. Struewing,Nigel K. Spurr,D. Timothy Bishop,J. G. M. Klijn,Peter Devilee,Cornelisse J. Cornelisse,Christine Lasset,Gilbert M. Lenoir,Rosa B. Barkardottir,Valgurdur Egilsson,Ute Hamann,Jenny Chang-Claude,Hagay Sobol,Barbara L. Weber,Michael R. Stratton,Douglas F. Easton +40 more
TL;DR: Key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCa2 genes are identified and this information may improve the classification of breast cancer in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
Journal ArticleDOI
KORA--a research platform for population based health research.
TL;DR: The KORA infrastructure, aspects of data management and quality control, and the concept of cooperative research are presented.
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