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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Journal ArticleDOI
Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair IMPLICATIONS FOR FANCONI ANEMIA AND BREAST CANCER SUSCEPTIBILITY
TL;DR: It is reported that RAD51C deficiency leads to ICL sensitivity, chromatid-type errors, and G(2)/M accumulation, which are hallmarks of the FA phenotype, and the critical role of RAD 51C in the FA pathway of ICL repair and as a tumor suppressor is unraveled.
Journal ArticleDOI
Fanconi anemia signaling network regulates the spindle assembly checkpoint
Grzegorz Nalepa,Rikki Enzor,Zejin Sun,Christophe Marchal,Su Jung Park,Yanzhu Yang,Laura Tedeschi,Stephanie Kelich,Helmut Hanenberg,Helmut Hanenberg,D. Wade Clapp +10 more
TL;DR: It is found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy and the essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuPLoidsy and malignant transformation known to occur after disruption of FA signaling.
Journal ArticleDOI
Rare genetic variants and the risk of cancer.
Walter F. Bodmer,Ian Tomlinson +1 more
TL;DR: There are good reasons to expect that common genetic variants do not explain all of the inherited risk of the common cancers, not least of these being the relatively low proportion of familial relative risk that common cancer SNPs currently explain.
Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene
Jung Young Park,Elizabeth L. Virts,Anna M. Jankowska,Constanze Wiek,Mohamed I. A. Othman,Sujata Chakraborty,Gail H. Vance,Fowzan S. Alkuraya,Helmut Hanenberg,Helmut Hanenberg,Helmut Hanenberg,Paul R. Andreassen,Paul R. Andreassen +12 more
TL;DR: Wild-type XRCC2 corrects each of three phenotypes characteristic of FA cells, all related to the repair of DNA interstrand crosslinks, including increased sensitivity to mitomycin C, chromosome breakage and G2–M accumulation in the cell cycle, and yields important insights into phenotypes related to FA and its genetic origins.
Journal ArticleDOI
Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.
Ella R. Thompson,Samantha E. Boyle,Julie Johnson,Julie Johnson,Georgina L Ryland,Georgina L Ryland,S Sawyer,David Y.H. Choong,kConFab,Georgia Chenevix-Trench,Alison H. Trainer,Geoffrey J. Lindeman,Geoffrey J. Lindeman,Gillian Mitchell,Paul A. James,Ian G. Campbell,Ian G. Campbell +16 more
TL;DR: A large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer, confirms a consistent but low frequency of inactivating RAD 51C mutations and provides support for the designation of the missense variant p.Gly264Ser as a moderate penetrance allele.
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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