Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel
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The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.
KeywordsGermline mutations Recurring mutations, BRCA1 BRCA2 High risk non Ashkenazi families
This study was partially funded by a grant to the Israeli consortium for hereditary breast cancer by the Israel Cancer Association to Eitan Friedman. This work was done in partial fulfillment of the requirements for the Masters degree for Anya Kushnir at the Department of Human Genetics and Molecular Biology at the Tel-Aviv University, Tel-Aviv, Israel.
Conflict of interest
All authors declare that they have no conflict of interest regarding the data published herein.
- 3.Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching N, Peretz T (1997) The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 60(3):505–514PubMedGoogle Scholar
- 5.Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, Ozcelik H, Goss P, Allingham-Hawkins D, Hamel N, Di Prospero L, Contiga V, Serruya C, Klein M, Moslehi R, Honeyford J, Liede A, Glendon G, Brunet JS, Narod S (1999) Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91(14):1241–1247PubMedCrossRefGoogle Scholar
- 7.Kauff ND, Perez-Segura P, Robson ME, Scheuer L, Siegel B, Schluger A, Rapaport B, Frank TS, Nafa K, Ellis NA, Parmigiani G, Offit K (2002) Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. J Med Genet 39(8):611–614PubMedCrossRefGoogle Scholar
- 8.Palma MD, Domchek SM, Stopfer J, Erlichman J, Siegfried JD, Tigges-Cardwell J, Mason BA, Rebbeck TR, Nathanson KL (2008) The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 68(17):7006–7014PubMedCrossRefGoogle Scholar
- 9.Neuhausen SL, Ozcelik H, Southey MC, John EM, Godwin AK, Chung W, Iriondo-Perez J, Miron A, Santella RM, Whittemore A, Andrulis IL, Buys SS, Daly MB, Hopper JL, Seminara D, Senie RT, Terry MB, Breast Cancer Family Registry (2009) BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research. Breast Cancer Res Treat 116(2):379–386PubMedCrossRefGoogle Scholar
- 10.Shiri-Sverdlov R, Gershoni-Baruch R, Ichezkel-Hirsch G, Gotlieb WH, Bruchim Bar-Sade R, Chetrit A, Rizel S, Modan B, Friedman E (2001) The Tyr978X BRCA1 mutation in non-Ashkenazi Jews: occurrence in high-risk families, general population and unselected ovarian cancer patients. Community Genet 4(1):50–55PubMedCrossRefGoogle Scholar
- 12.Laitman Y, Borsthein RT, Stoppa-Lyonnet D, Dagan E, Castera L, Goislard M, Gershoni-Baruch R, Goldberg H, Kaufman B, Ben-Baruch N, Zidan J, Maray T, Soussan-Gutman L, Friedman E (2011) Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat 127(2):489–495PubMedCrossRefGoogle Scholar
- 14.Górski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, Gronwald J, Pluzańska A, Bebenek M, Fischer-Maliszewska L, Grzybowska E, Narod SA, Lubiński J (2000) Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet 66(6):1963–1968PubMedCrossRefGoogle Scholar
- 15.Górski B, Cybulski C, Huzarski T, Byrski T, Gronwald J, Jakubowska A, Stawicka M, Gozdecka-Grodecka S, Szwiec M, Urbański K, Mituś J, Marczyk E, Dziuba J, Wandzel P, Surdyka D, Haus O, Janiszewska H, Debniak T, Tołoczko-Grabarek A, Medrek K, Masojć B, Mierzejewski M, Kowalska E, Narod SA, Lubiński J (2005) Breast cancer predisposing alleles in Poland. Breast Cancer Res Treat 92(1):19–24PubMedCrossRefGoogle Scholar
- 18.Elsakov P, Kurtinaitis J, Petraitis S, Ostapenko V, Razumas M, Razumas T, Meskauskas R, Petrulis K, Luksite A, Lubiński J, Górski B, Narod SA, Gronwald J (2010) The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet 78(4):373–376PubMedCrossRefGoogle Scholar
- 21.Shiri-Sverdlov R, Oefner P, Green L, Baruch RG, Wagner T, Kruglikova A, Haitchick S, Hofstra RM, Papa MZ, Mulder I, Rizel S, Bar Sade RB, Dagan E, Abdeen Z, Goldman B, Friedman E (2000) Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer. Hum Mutat 16(6):491–501PubMedCrossRefGoogle Scholar
- 25.Behar DM, Yunusbayev B, Metspalu M, Metspalu E, Rosset S, Parik J, Rootsi S, Chaubey G, Kutuev I, Yudkovsky G, Khusnutdinova EK, Balanovsky O, Semino O, Pereira L, Comas D, Gurwitz D, Bonne-Tamir B, Parfitt T, Hammer MF, Skorecki K, Villems R (2010) The genome-wide structure of the Jewish people. Nature 466(7303):238–242PubMedCrossRefGoogle Scholar
- 26.Atzmon G, Hao L, Pe’er I, Velez C, Pearlman A, Palamara PF, Morrow B, Friedman E, Oddoux C, Burns E, Ostrer H (2010) Abraham’s children in the genome era: major Jewish diaspora populations comprise distinct genetic clusters with shared middle eastern ancestry. Am J Hum Genet 86(6):850–859PubMedCrossRefGoogle Scholar
- 27.Wang F, Fang Q, Ge Z, Yu N, Xu S, Fan X (2011) Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review. Mol Biol Rep [Epub ahead of print]Google Scholar