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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Detection of a pathogenic Alu element insertion in PALB2 gene from targeted NGS diagnostic data
Mélanie Eyries,Olivier Ariste,Gaelle Legrand,Noémie Basset,Erell Guillerm,Alexandre Perrier,C. Duros,Odile Cohen-Haguenauer,P. de la Grange,Florence Coulet +9 more
TL;DR: Retrospective analysis of targeted next-generation sequencing data from 359 patients was performed to detect the first report of a pathogenic MEI in PALB2, demonstrating that MEI analysis may help to improve molecular diagnostic yield and can be performed from targeted NGS data used for routine diagnosis.
Journal ArticleDOI
Inherited rare variants in homologous recombination and neurodevelopmental genes are associated with increased risk of neuroblastoma
Ferdinando Bonfiglio,Vito Alessandro Lasorsa,Sueva Cantalupo,Giuseppe D'Alterio,Vincenzo Aievola,Angelo Boccia,Martina Ardito,Simone Furini,Alessandra Renieri,Martina Morini,Sabine A Stainczyk,Frank Westermann,Giovanni Paolella,Alessandra Eva,Achille Iolascon,Mario Capasso +15 more
TL;DR: In this paper , the authors conducted whole-exome sequencing (WES) of 664 NB cases and 822 controls and used independent validation datasets to identify genes with rare risk variants and involved pathways.
Journal ArticleDOI
Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report
Mashu Futagawa,Hideki Yamamoto,Mariko Kochi,Yusaku Urakawa,Reimi Sogawa,Fumino Kato,Mika Okazawa-Sakai,Daisuke Ennishi,Katsunori Shinozaki,Hirofumi Inoue,Hiroyuki Yanai,Akira Hirasawa +11 more
TL;DR: In this paper, a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D was reported.
Journal ArticleDOI
Thiopurine-induced mitotic catastrophe in Rad51d-deficient mammalian cells.
Michael D. Wyatt,Nicole M. Reilly,Shikha Patel,Preeti Rajesh,Gary P. Schools,Phillip G. Smiraldo,Douglas L. Pittman +6 more
TL;DR: It is demonstrated that RAD51D is required for maintaining the telomeric 3′ overhangs, and a unique window into the role of the RAD 51D HR protein during thiopurine induction of mitotic catastrophe is provided.
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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