Breast and Ovarian Cancer Risk and Risk Reduction in Jewish <i>BRCA1/2</i> Mutation Carriers

Finkelman, Brian S.; Rubinstein, Wendy S.; Friedman, Sue; Friebel, Tara M.; Dubitsky, Shera; Schonberger, Niecee Singer; Shoretz, Rochelle; Singer, Christian F.; Blum, Joanne L.; Tung, Nadine; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Snyder, Carrie; Garber, Judy E.; Schildkraut, Joellen M.; Daly, Mary B.; Isaacs, Claudine; Pichert, Gabrielle; Neuhausen, Susan L.; Couch, Fergus J.; Veer, Laura van’t; Eeles, Rosalind; Bancroft, Elizabeth; Evans, D. Gareth; Ganz, Patricia A.; Tomlinson, Gail E.; Narod, Steven A.; Matloff, Ellen; Domchek, Susan M.; Rebbeck, Timothy R.

doi:10.1200/jco.2011.37.8133

Cited by 34 publications

(32 citation statements)

References 48 publications

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“…Risks of breast and ovarian cancer to females with BRCA1 mutations ascertained via these healthy males were comparable to risk estimates in previous studies with ascertainment through affected index cases (SI Appendix, Table S6) (3,20,22). In contrast, a notable difference between this and other studies is that BRCA2 mutation carriers in this study have a higher risk of ovarian cancer and a lower risk of breast cancer than do BRCA2 mutation carriers in other studies (SI Appendix, Tables S6 and S7) (2,16). Differences in site of first cancer may reflect a lower prevalence in the Israeli population of nongenetic risk factors for breast cancer, such as late age at first pregnancy, and therefore reduced competing risk.…”

Section: Discussionsupporting

confidence: 84%

“…In comparison, for the Israeli AJ female population born between 1920 and 1950 (i.e., the generation of the mothers of the index subjects), the Israeli Cancer Registry reported (1). A subset of noncarriers was matched to carriers for age, area of residence, and recruitment locale (2). Of the 175 male index subjects with mutations, 3 were related to another carrier, so 172 families were represented.…”

Section: Resultsmentioning

confidence: 99%

“…genomics I nherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancer. Among female mutation carriers, presymptomatic surgical measures significantly reduce morbidity and mortality (1,2). In particular, risk-reducing salpingo-oophorectomy (i.e., the removal of ovaries and fallopian tubes from a woman without ovarian cancer) reduces risk both of breast cancer and of ovarian cancer, as well as overall mortality (1).…”

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confidence: 99%

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Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Gabai-Kapara

Lahad

Kaufman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

315

275

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In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingooophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations. genomics I nherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancer. Among female mutation carriers, presymptomatic surgical measures significantly reduce morbidity and mortality (1, 2). In particular, risk-reducing salpingo-oophorectomy (i.e., the removal of ovaries and fallopian tubes from a woman without ovarian cancer) reduces risk both of breast cancer and of ovarian cancer, as well as overall mortality (1). However, for many mutation carriers identified following their first cancer diagnosis, genetic testing was not previously indicated because family history did not suggest inherited cancer predisposition (3)(4)(5)6). From a prevention perspective, it is a missed opportunity to identify a woman as a BRCA1 or BRCA2 mutation carrier only after she develops cancer.Among Ashkenazi (European) Jews (AJ), three mutations, BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, account for the great majority of inherited cancer risk due to BRCA1 and BRCA2 (7). In the AJ population, 2.5% of persons carry one of these three mutations (8), and the mutations account for 11% of breast cancer (3) and 40% of ovarian cancer (9, 10). These observations suggest that genetic testing in the AJ population for these mutations fulfills WHO criteria for population screening (11, 12): The disease is an important public health burden to the target popu...

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Gabai-Kapara

Lahad

Kaufman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

315

275

View full text Add to dashboard Cite

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“…For ovarian cancer, BRCA1 is associated with a 36-63% lifetime risk as opposed to 10-27% for BRCA2 carriers. 1 Various mutations in BRCA1/2 specific to particular ethnic populations have been described. About 2.5% of Ashkenazi Jews carry one of the three founder mutations: BRCA1 185delAG (c.66_67delAG, p.Glu23fs), BRCA1 5382insC (c.5263insC, p.Gln1756fs), and BRCA2 6174delT (c.5946delT, p.Ser1982fs).…”

mentioning

confidence: 99%

Molecular testing for the BRCA1 and BRCA2 Ashkenazi Jewish founder mutations: a report on the College of American Pathologists proficiency testing surveys

Tafe

Datto

Palomaki

et al. 2015

Genetics in Medicine

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“…Of principal interest is the penetrance of the 6174delT mutation, which appears to be lower than that of other BRCA2 mutations 15 . Antoniou et al 15 estimate the penetrance of this mutation to be 43% to age 70; Finkelman et al 16 estimate it to be 55%. Further, the risk of cancer in the mutation carriers varies according to family history, in particular for BRCA2 carriers, but the extent of the increase in risk with each affected relative is not yet clear 17 .…”

Section: Are Current Cancer Risk Management Strategies Appropriate Fomentioning

confidence: 99%

Is It Time to Offer BRCA1 and BRCA2 Testing to All Jewish Women?

et al. 2015

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It was 2007 when Women's College Hospital first began to test for BRCA1 and BRCA2 mutations among all Jewish women in Ontario. On a research basis, testing was performed regardless of personal or family history of cancer for three recurrent Jewish founder BRCA mutations 1 . To date, more than 7000 women have been tested, and the program remains active. Recently, two studies have supported the conclusion that population-based testing is a rational approach to identifying BRCA mutation carriers. In an Israeli study of 8105 unselected Jewish men 2 and a British study of 1034 unselected Jewish men and women 3 , more than one half of the identified mutation carriers failed to qualify for genetic testing based on family history. Much in the news, Mary-Claire King has highlighted the results of the Israeli study to support the position that genetic testing for BRCA1 and BRCA2 should be offered to all women, and not just to Jews 4 . Her recommendation is based on the finding that the cancer risks associated with a BRCA mutation are high even in the absence of a family history of cancer 2 . Critics of population-based testing say that more research has to be done before that recommendation can be entertained.Over the course of the past 10 years, our group has tried to accumulate evidence to answer the relevant questions. Dr. Robert Nuttall, assistant director of cancer control policy at the Canadian Cancer Society, told The Canadian Jewish News that "while genetic screening can identify women at high risk for cancer, there are still questions that need to be addressed before genetic screening is made available to the Ashkenazi Jewish population." Here, we address his questions. Who Constitutes the Appropriate Target Population?Considered together, two mutations in BRCA1 and one mutation in BRCA2 are present in up to 2.5% of Ashkenazi Jewish women 5,6 . Those three mutations represent a preponderance of the deleterious mutations in the Jewish population 7,8 . Genetic testing for the "founder" panel is relatively straightforward and inexpensive. In our study of more than 6000 unselected Jewish women, only 38% of the women who were found to have a BRCA mutation would have qualified for genetic testing based on current genetic testing guidelines 7 . That finding was recently confirmed in Israel and Britain 2,8 . Most women with mutations are not being identified because of a historical reliance on personal and family history of cancer-a policy that goes back to the 1990s and that fails to take into account advances in molecular techniques.Our experience is Ontario-based, but should be relevant for Jewish populations elsewhere. The utility of testing will depend to a large degree on the cost of the test provided and of the regional health care system. We do not argue that costs must be covered by a third-party payer (for example, the Canadian public health care system); it could be that the most efficient delivery of services will be based on direct-to-consumer testing offered by a private laboratory. Various scenarios should...

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Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers

Cited by 34 publications

References 48 publications

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Molecular testing for the BRCA1 and BRCA2 Ashkenazi Jewish founder mutations: a report on the College of American Pathologists proficiency testing surveys

Is It Time to Offer BRCA1 and BRCA2 Testing to All Jewish Women?

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