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Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel

  • Epidemiology
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Abstract

Three mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) predominate among high risk breast ovarian cancer Ashkenazi Jewish families, with few “private” mutations described. Additionally, the spectrum of BRCA1 and BRCA2 germline mutations among high risk Jewish non Ashkenazi and non Jewish Israelis is undetermined. Genotyping by exon-specific sequencing or heteroduplex analysis using enhanced mismatch mutation analysis was applied to 250 high risk, predominantly cancer affected, unrelated Israeli women of Ashkenazi (n = 72), non Ashkenazi (n = 90), Moslem (n = 45), Christian Arabs (n = 21), Druze (n = 17), and non Jewish Caucasians (n = 5). All Jewish women were prescreened and did not harbor any of the predominant BRCA1 or BRCA2 Jewish mutations. Age at diagnosis of breast cancer (median ± SD) (n = 219) was 40.1 ± 11.7, 45.6 ± 10.7, 38.7 ± 9.2, 45.5 ± 11.4 ± and 40.7 ± 8.1 years for Ashkenazi, non Ashkenazi, Moslem, Christian, and Druze participants, respectively. For ovarian cancer (n = 19) the mean ages were 45.75 ± 8.2, 57.9 ± 10.1, 54 ± 8, 70 ± 0, and 72 ± 0 for these origins, respectively. Overall, 22 (8.8%) participants carried 19 clearly pathogenic mutations—10 BRCA1 and 9 BRCA2 (3 novel): 3 in Ashkenazim, 6 in 8 non-Ashkenazim, 6 in 7 Moslems, 2 in Druze, and 2 in non Jewish Caucasians. Only three mutations (c.1991del4, C61G, A1708E) were detected in 2 seemingly unrelated families of Moslem and non- Ashkenazi origins. There were no inactivating mutations among 55 Ashkenazi high risk breast cancer only families. In conclusion, there are no predominant recurring germline mutations in BRCA1 or BRCA2 genes among ethnically diverse Jewish and non Jewish high risk families in Israel.

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References

  1. Petrucelli N, Daly MB, Feldman GL (2010) Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med 12(5):245–259

    Article  PubMed  CAS  Google Scholar 

  2. Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjörd JE (1998) Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352(9137):1337–1339

    Article  PubMed  CAS  Google Scholar 

  3. 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):19–24

    Article  PubMed  Google Scholar 

  4. Sokolenko AP, Mitiushkina NV, Buslov KG, Bit-Sava EM, Iyevleva AG, Chekmariova EV, ESh Kuligina, Ulibina YM, Rozanov ME, Suspitsin EN, Matsko DE, Chagunava OL, Trofimov DY, Devilee P, Cornelisse C, Togo AV, Semiglazov VF, Imyanitov EN (2006) High frequency of BRCA1 5382insC mutation in Russian breast cancer patients. Eur J Cancer 42(10):1380–1384

    Article  PubMed  CAS  Google Scholar 

  5. Heimdal K, Maehle L, Apold J, Pedersen JC, Møller P (2003) The Norwegian founder mutations in BRCA1: high penetrance confirmed in an incident cancer series and differences observed in the risk of ovarian cancer. Eur J Cancer 39(15):2205–2213

    Article  PubMed  CAS  Google Scholar 

  6. 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):505–514

    PubMed  CAS  Google Scholar 

  7. Tobias DH, Eng C, McCurdy LD, Kalir T, Mandelli J, Dottino PR, Cohen CJ (2000) Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients. Gynecol Oncol 78(2):148–151

    Article  PubMed  CAS  Google Scholar 

  8. 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):1241–1247

    Article  PubMed  CAS  Google Scholar 

  9. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA (1999) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64(4):963–970

    Article  PubMed  CAS  Google Scholar 

  10. 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):611–614

    Article  PubMed  CAS  Google Scholar 

  11. 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):7006–7014

    Article  PubMed  Google Scholar 

  12. 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):50–55

    Article  PubMed  Google Scholar 

  13. Lerer I, Wang T, Peretz T, Sagi M, Kaduri L, Orr-Urtreger A, Stadler J, Gutman H, Abeliovich D (1998) The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. Am J Hum Genet 63(1):272–274

    Article  PubMed  CAS  Google Scholar 

  14. Tarabeia J, Baron-Epel O, Barchana M, Liphshitz I, Ifrah A, Fishler Y, Green MS (2007) A comparison of trends in incidence and mortality rates of breast cancer, incidence to mortality ratio and stage at diagnosis between Arab and Jewish women in Israel, 1979–2002. Eur J Cancer Prev 16(1):36–42

    Article  PubMed  Google Scholar 

  15. Nissan A, Spira RM, Hamburger T, Badriyyah M, Prus D, Cohen T, Hubert A, Freund HR, Peretz T (2004) Clinical profile of breast cancer in Arab and Jewish women in the Jerusalem area. Am J Surg 188:62–67

    Article  PubMed  Google Scholar 

  16. Ibrahim EM, al-Mulhim FA, al-Amri A, al-Muhanna FA, Ezzat AA, Stuart RK, Ajarim D (1998) Breast cancer in the eastern province of Saudi Arabia. Med Oncol 15:241–247

    Article  PubMed  CAS  Google Scholar 

  17. El-Harith el HA, Abdel-Hadi MS, Steinmann D, Dork T (2000) BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia. Saudi Med J 23:700–704

    Google Scholar 

  18. Kadouri L, Bercovich D, Elimelech A, Lerer I, Sagi M, Glusman G, Shochat C, Korem S, Hamburger T, Nissan A, Abu-Halaf N, Badrriyah M, Abeliovich D, Peretz T (2007) A novel BRCA-1 mutation in Arab kindred from east Jerusalem with breast and ovarian cancer. BMC Cancer 7:14

    Google Scholar 

  19. Atoum MF, Al-Kayed SA (2004) Mutation analysis of the breast cancer gene BRCA1 among breast cancer Jordanian females. Saudi Med J 25(1):60–63

    PubMed  Google Scholar 

  20. Troudi W, Uhrhammer N, Sibille C, Dahan C, Mahfoudh W, Bouchlaka Souissi C, Jalabert T, Chouchane L, Bignon YJ, Ben Ayed F, Ben Ammar Elgaaied A (2007) Contribution of the BRCA1 and BRCA2 mutations to breast cancer in Tunisia. J Hum Genet 52(11):915–920

    Article  PubMed  CAS  Google Scholar 

  21. Eachkoti R, Hussain I, Afroze D, Aejazaziz S, Jan M, Shah ZA, Das BC, Siddiqi MA (2007) BRCA1 and TP53 mutation spectrum of breast carcinoma in an ethnic population of Kashmir, an emerging high-risk area. Cancer Lett 248(2):308–320

    Article  PubMed  CAS  Google Scholar 

  22. Troudi W, Uhrhammer N, Romdhane KB, Sibille C, Amor MB, Khodjet El Khil H, Jalabert T, Mahfoudh W, Chouchane L, Ayed FB, Bignon YJ, Elgaaied AB (2008) Complete mutation screening and haplotype characterization of BRCA1 gene in Tunisian patients with familial breast cancer. Cancer Biomark 4(1):11–18

    PubMed  CAS  Google Scholar 

  23. Uhrhammer N, Abdelouahab A, Lafarge L, Feillel V, Ben Dib A, Bignon YJ (2008) BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases. Int J Med Sci 5(4):197–202

    PubMed  CAS  Google Scholar 

  24. Moattar T, Kausar T, Aban M, Khan S, Pervez S (2006) Medullary carcinoma of breast with a novel germline mutation 1123T>G in exon 11 of BRCA1. J Coll Physicians Surg Pak 16(9):606–607

    PubMed  Google Scholar 

  25. Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA (2002) Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. Am J Hum Genet 71(3):595–606

    Article  PubMed  CAS  Google Scholar 

  26. Rashid MU, Zaidi A, Torres D, Sultan F, Benner A, Naqvi B, Shakoori AR, Seidel-Renkert A, Farooq H, Narod S, Amin A, Hamann U (2006) Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients. Int J Cancer 119(12):2832–2839

    Article  PubMed  CAS  Google Scholar 

  27. Nissim D (2003) The Druze in the Middle East: their faith, leadership, identity and status. Sussex Academic Press, Brighton, pp 227. ISBN: 978-1903900369

  28. Lynch HT, Watson P, Tinley S, Snyder C, Durham C, Lynch J, Kirnarsky Y, Serova O, Lenoir G, Lerman C, Narod SA (1999) An update on DNA-based BRCA1/BRCA2 genetic counseling in hereditary breast cancer. Cancer Genet Cytogenet 109:91–98

    Article  PubMed  CAS  Google Scholar 

  29. 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):491–501

    Article  PubMed  CAS  Google Scholar 

  30. Soegaard M, Kjaer SK, Cox M, Wozniak E, Høgdall E, Høgdall C, Blaakaer J, Jacobs IJ, Gayther SA, Ramus SJ (2008) BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark. Clin Cancer Res 14(12):3761–3767

    Article  PubMed  CAS  Google Scholar 

  31. Houdayer C, Moncoutier V, Champ J, Weber J, Viovy JL, Stoppa-Lyonnet D (2010) Enhanced mismatch mutation analysis: simultaneous detection of point mutations and large scale rearrangements by capillary electrophoresis, application to BRCA1 and BRCA2. Methods Mol Biol 653:147–180

    Article  PubMed  CAS  Google Scholar 

  32. Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20(6):1480–1490

    Article  PubMed  CAS  Google Scholar 

  33. Denic S, Al-Gazali L (2002) Breast cancer, consanguinity, and lethal tumor genes: simulation of BRCA1/2 prevalence over 40 generations. Int J Mol Med 10(6):713–719

    PubMed  CAS  Google Scholar 

  34. Moncoutier V, Castera L, Tirapo C, Michaux D, Remon MA, Laugé A, Rouleau E, de Pauw A, Buecher B, Gauthier-Villars M, Viovy JL, Stoppa-Lyonnet D, Houdayer C (2010) EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat (submitted)

  35. Distelman-Menachem T, Shapira T, Laitman Y, Kaufman B, Barak F, Tavtigian S, Friedman E (2009) Analysis of BRCA1/BRCA2 genes’ contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women. Fam Cancer 8(2):127–133

    Article  PubMed  CAS  Google Scholar 

  36. Kaufman B, Laitman Y, Carvalho MA, Edelman L, Menachem TD, Zidan J, Monteiro AN, Friedman E (2006) The P1812A and P25T BRCA1 and the 5164del4 BRCA2 mutations: occurrence in high-risk non-Ashkenazi Jews. Genet Test 10(3):200–207

    Article  PubMed  CAS  Google Scholar 

  37. Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T, Samollow PB, de Silva D, Zharkikh A, Thomas A (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43:295–305

    Article  PubMed  CAS  Google Scholar 

  38. Katagiri T, Kasumi F, Yoshimoto M, Nomizu T, Asaishi K, Abe R, Tsuchiya A, Sugano M, Takai S, Yoneda M, Fukutomi T, Nanba K, Makita M, Okazaki H, Hirata K, Okazaki M, Furutsuma Y, Morishita Y, Iino Y, Karino T, Ayabe H, Hara S, Kajiwara T, Houga S, Shimizu T, Toda M, Ymazaki Y, Uchida T, Kunimoto K, Sonoo H, Kurebayashi J-I, Shimtsuma K, Nakamura Y, Miki Y (1998) High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families. J Hum Genet 43(1):42–48

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Yael Laitman & Eitan Friedman

  2. The Genetics Institute, Rambam Medical Center, Haifa, Israel

    Roni Tsipora Borsthein, Efrat Dagan & Ruth Gershoni-Baruch

  3. Département de Biologie, Institut Curie, Hôpital, Paris, 75248, France

    Dominique Stoppa-Lyonnet, Laurent Castera & Maud Goislard

  4. INSERM U830, Paris, 75248, France

    Dominique Stoppa-Lyonnet

  5. Université Paris Descartes, Paris, 75270, France

    Dominique Stoppa-Lyonnet

  6. Oncology Institute, Rambam Medical Center, Haifa, Israel

    Hadassah Goldberg

  7. The Oncology Institute, Sheba Medical Center, Haifa, Israel

    Bella Kaufman

  8. The Oncology Institute, Kaplan Medical Center, Rehovot, Israel

    Noa Ben-Baruch

  9. The Oncology Institute, Ziv Medical Center, Safed, Israel

    Jamal Zidan

  10. Golan for Development of the Arab Villages (GfD), Majdal Shams, 12438, Golan Heights, Israel

    Taiseer Maray

  11. Oncotest Teva, Netanya, Israel

    Lior Soussan-Gutman

  12. The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Bella Kaufman & Eitan Friedman

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  1. Yael Laitman
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Correspondence to Eitan Friedman.

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Laitman, Y., Borsthein, R.T., Stoppa-Lyonnet, D. et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat 127, 489–495 (2011). https://doi.org/10.1007/s10549-010-1217-0

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