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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer
Victor Abkevich,Kirsten Timms,Bryan T. Hennessy,Jennifer Potter,Mark S. Carey,Larissa A. Meyer,Karen Smith-McCune,Russell Broaddus,Karen H. Lu,Jian Chen,Thanh Tran,Dominic P. Williams,Diana Iliev,Srikanth Jammulapati,Lisa M. Fitzgerald,Thomas C. Krivak,Julie A. DeLoia,Alexander Gutin,Gordon B. Mills,Jerry S. Lanchbury +19 more
TL;DR: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism, which could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.
Journal ArticleDOI
Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer
Kelly L. Bolton,Kelly L. Bolton,Georgia Chenevix-Trench,Cindy Goh,Siegal Sadetzki,Susan J. Ramus,Beth Y. Karlan,Diether Lambrechts,Evelyn Despierre,Daniel Barrowdale,Lesley McGuffog,Sue Healey,Douglas F. Easton,Olga M. Sinilnikova,Javier Benitez,María Jesús Gómez García,Susan L. Neuhausen,Mitchell H. Gail,Patricia Hartge,Susan Peock,Debra Frost,D. Gareth Evans,Rosalind A. Eeles,Andrew K. Godwin,Mary B. Daly,Ava Kwong,Ava Kwong,Edmond S. K. Ma,Conxi Lázaro,Ignacio Blanco,Marco Montagna,Emma D'Andrea,Maria Ornella Nicoletto,Sharon E. Johnatty,Susanne K. Kjaer,Allan Jensen,Estrid Høgdall,Ellen L. Goode,Brooke L. Fridley,Jennifer T. Loud,Mark H. Greene,Phuong L. Mai,Angela Chetrit,Flora Lubin,Galit Hirsh-Yechezkel,Gord Glendon,Irene L. Andrulis,Irene L. Andrulis,Amanda E. Toland,Leigha Senter,Martin Gore,Charlie Gourley,Caroline O. Michie,Honglin Song,Jonathan Tyrer,Alice S. Whittemore,Valerie McGuire,Weiva Sieh,Ulf Kristoffersson,Håkan Olsson,Åke Borg,Douglas A. Levine,Linda Steele,Mary S. Beattie,Salina Chan,Robert L. Nussbaum,Kirsten B. Moysich,Jenny Gross,Ilana Cass,Christine Walsh,Andrew J. Li,R.S. Leuchter,Ora Gordon,Montserrat Garcia-Closas,Simon A. Gayther,Stephen J. Chanock,Antonis C. Antoniou,Paul D.P. Pharoah +77 more
TL;DR: Among patients with invasive EOC, having a germline mutation in BRCA1 or BRC a2 was associated with improved 5-year overall survival and BRCa2 carriers had the best prognosis.
Journal ArticleDOI
Fanconi anaemia and the repair of Watson and Crick DNA crosslinks
TL;DR: The function of Fanconi anaemia proteins is to maintain genomic stability and their main role is in the repair of DNA interstrand crosslinks, which, by covalently binding the Watson and the Crick strands of DNA, impede replication and transcription.
Journal ArticleDOI
Germline mutations in RAD51D confer susceptibility to ovarian cancer
Chey Loveday,Clare Turnbull,Emma Ramsay,Deborah Hughes,Elise Ruark,Jessica Frankum,Georgina Bowden,Bolot Kalmyrzaev,Margaret Warren-Perry,Katie Snape,Julian Adlard,Julian Barwell,Jonathan Berg,Angela F. Brady,Carole Brewer,G Brice,C Chapman,Jackie Cook,Rosemarie Davidson,Alan Donaldson,Fiona Douglas,Lynn Greenhalgh,Alex Henderson,Louise Izatt,Ajith Kumar,Fiona Lalloo,Zosia Miedzybrodzka,Patrick J. Morrison,Joan Paterson,Mary Porteous,Mark T. Rogers,Susan Shanley,Lisa Walker,Diana Eccles,D. Gareth Evans,Anthony Renwick,Sheila Seal,Christopher J. Lord,Alan Ashworth,Jorge S. Reis-Filho,Antonis C. Antoniou,Nazneen Rahman +41 more
TL;DR: It is shown that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD 51D mutation carriers.
Journal ArticleDOI
Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment
Allison W. Kurian,Emily E. Hare,Meredith A. Mills,Kerry Kingham,Lisa A. McPherson,Alice S. Whittemore,Valerie McGuire,Uri Ladabaum,Yuya Kobayashi,Stephen E Lincoln,Michele Cargill,James M. Ford +11 more
TL;DR: Results suggest that multiple-gene sequencing may benefit appropriately selected patients, and additional studies are required to quantify the penetrance of identified mutations and determine clinical utility.
References
More filters
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.
Related Papers (5)
A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1
Yoshio Miki,Jeff Swensen,Donna M Shattuck-Eidens,P. Andrew Futreal,Keith D Harshman,Sean V. Tavtigian,Qingyun Liu,Charles Cochran,L. Michelle Bennett,Wei Ding,Russell Bell,Judith Rosenthal,Charles E. Hussey,Thanh Tran,Melody McClure,Cheryl Frye,Tom Hattier,Robert Phelps,Astrid Haugen-Strano,Harold Katcher,Kazuko Yakumo,Zahra Gholami,Daniel Shaffer,Steven Stone,Steven Bayer,Christian Wray,Robert Bogden,Priya Dayananth,John R. Ward,Patricia N. Tonin,Steven A. Narod,Pam K. Bristow,Frank H. Norris,Leah M. Helvering,Paul Morrison,Paul Robert Rosteck,Mei Lai,J. Carl Barrett,Cathryn M. Lewis,Susan L. Neuhausen,Lisa A. Cannon-Albright,David E. Goldgar,Roger W. Wiseman,Alexander Kamb,Mark H. Skolnick +44 more
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies
Antonis C. Antoniou,Paul D.P. Pharoah,Steven A. Narod,Harvey A. Risch,Jorunn E. Eyfjord,John L. Hopper,Niklas Loman,Håkan Olsson,Oskar T. Johannsson,Åke Borg,Barbara Pasini,Paolo Radice,Siranoush Manoukian,Diana Eccles,Nelson L.S. Tang,E. Olah,Hoda Anton-Culver,Ellen Warner,Jan Lubinski,Jacek Gronwald,Bohdan Górski,Hrafn Tulinius,Steinunn Thorlacius,Hannaleena Eerola,Heli Nevanlinna,Kirsi Syrjäkoski,Olli Kallioniemi,Deborah J. Thompson,Christopher H. Evans,Julian Peto,Julian Peto,Fiona Lalloo,D G R Evans,Douglas F. Easton +33 more