Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families
D Ford,Douglas F. Easton,Michael R. Stratton,Steven A. Narod,David E. Goldgar,Peter Devilee,D. T. Bishop,Barbara L. Weber,Gilbert M. Lenoir,Jenny Chang-Claude,Hagay Sobol,M D Teare,Jeffery P. Struewing,Adalgeir Arason,Siegfried Scherneck,Julian Peto,Timothy R. Rebbeck,Patricia N. Tonin,Susan L. Neuhausen,Rosa B. Barkardottir,Jorunn E. Eyfjord,Henry T. Lynch,Bruce A.J. Ponder,Simon A. Gayther,J.M. Birch,Annika Lindblom,Dominique Stoppa-Lyonnet,Y. J. Bignon,Åke Borg,U Hamann,Neva E. Haites,Rodney J. Scott,Christine Maugard,Hans F. A. Vasen,Susanne Seitz,Lisa A. Cannon-Albright,Andrew Craig Schofield,Moraima Zelada-Hedman +37 more
TLDR
The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in bRCA2 carriers <50 years of age.Abstract:
The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.read more
Citations
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Journal ArticleDOI
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
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
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
Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers
Karoline Kuchenbaecker,Karoline Kuchenbaecker,John L. Hopper,Daniel R. Barnes,Kelly-Anne Phillips,T.M. Mooij,Marie-José Roos-Blom,Marie-José Roos-Blom,Sarah Jervis,Sarah Jervis,Flora E. van Leeuwen,Roger L. Milne,Roger L. Milne,Nadine Andrieu,David E. Goldgar,Mary Beth Terry,Matti A. Rookus,Douglas F. Easton,Antonis C. Antoniou,Lesley McGuffog,D. Gareth Evans,Daniel Barrowdale,Debra Frost,Julian Adlard,Kai-ren Ong,Louise Izatt,Marc Tischkowitz,Ros Eeles,Rosemarie Davidson,Shirley Hodgson,Steve Ellis,Catherine Noguès,Christine Lasset,Dominique Stoppa-Lyonnet,Dominique Stoppa-Lyonnet,Jean-Pierre Fricker,Laurence Faivre,Pascaline Berthet,Maartje J. Hooning,Lizet E. van der Kolk,Carolien M. Kets,Muriel A. Adank,Esther M. John,Wendy K. Chung,Irene L. Andrulis,Irene L. Andrulis,Melissa C. Southey,Mary B. Daly,Saundra S. Buys,Ana Osorio,Christoph Engel,Karin Kast,Rita K. Schmutzler,Trinidad Caldés,Anna Jakubowska,Jacques Simard,Michael Friedlander,Sue-Anne McLachlan,Sue-Anne McLachlan,Eva Machackova,Lenka Foretova,Yen Y. Tan,Yen Y. Tan,Christian F. Singer,Edith Olah,Anne-Marie Gerdes,Brita Arver,Håkan Olsson +67 more
TL;DR: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location, a large cohort study recruited in 1997-2011 provides estimates of cancer risk based on BRCA1 and BRCa2 mutation carrier status.
Journal ArticleDOI
Gene-Expression Profiles in Hereditary Breast Cancer
Ingrid Hedenfalk,David Duggan,Yi Chen,Michael D. Radmacher,M. Bittner,Richard M. Simon,P. Meltzer,Barry A. Gusterson,Manel Esteller,O. P. Kallioniemi,Benjamin S. Wilfond,Åke Borg,J.M. Trent,Mark Raffeld,Zohar Yakhini,Amir Ben-Dor,Edward R. Dougherty,Juha Kononen,Lukas Bubendorf,W Fehrle,Stefania Pittaluga,Sofia Gruvberger,Niklas Loman,Oskar T. Johannsson,Håkan Olsson,Guido Sauter +25 more
TL;DR: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancersWith BRCa2 mutations, the results suggest that a heritable mutation influences the gene-expression profile of the cancer.
Journal ArticleDOI
Meta-analysis of BRCA1 and BRCA2 penetrance
Sining Chen,Giovanni Parmigiani +1 more
TL;DR: A set of risk estimates for BRCa1 and BRCA2 mutation carriers that can be used by counselors and clinicians who are interested in advising patients based on a comprehensive set of studies rather than one specific study are provided.
References
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Journal ArticleDOI
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
TL;DR: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods.
Journal ArticleDOI
Identification of the breast cancer susceptibility gene BRCA2
Richard Wooster,Graham R. Bignell,Johnathan M. Lancaster,Sally Swift,Sheila Seal,Jonathon Mangion,N. Collins,Simon G. Gregory,Curtis Gumbs,Gos Micklem +9 more
TL;DR: The identification of a gene in which six different germline mutations in breast cancer families that are likely to be due to BRCA2 are detected, and results indicate that this is the BRC a2 gene.
Journal ArticleDOI
Strategies for multilocus linkage analysis in humans.
TL;DR: The results show that considerable economy and efficiency can be brought to the mapping endeavor by resorting to appropriate strategies of detecting linkage and by constructing the human genetic map on a common reference panel of families.
Journal ArticleDOI
Linkage of early-onset familial breast cancer to chromosome 17q21
TL;DR: Ch Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease, and genetic analysis yields a lod score of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-ONSet families and negative lod scores in familiesWith late-onsets disease.
Journal ArticleDOI
The Risk of Cancer Associated with Specific Mutations of BRCA1 and BRCA2 among Ashkenazi Jews
Jeffery P. Struewing,Patricia Hartge,Sholom Wacholder,Sonya M. Baker,Martha Berlin,Mary McAdams,Michelle M. Timmerman,Lawrence C. Brody,Margaret A. Tucker +8 more
TL;DR: The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.
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