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The yield of full BRCA1/2 genotyping in Israeli Arab high-risk breast/ovarian cancer patients

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

While the spectrum of germline mutations in BRCA1/2 genes in the Israeli Jewish population has been extensively studied, there is a paucity of data pertaining to Israeli Arab high-risk cases.

Methods

Consecutive Israeli Arab breast and/or ovarian cancer patients were recruited using an ethically approved protocol from January 2012 to February 2019. All ovarian cancer cases were referred for BRCA genotyping. Breast cancer patients were offered BRCA sequencing and deletion/duplication analysis after genetic counseling, if the calculated risk for carrying a BRCA mutation by risk prediction algorithms was ≥10%.

Results

Overall, 188 patients participated; 150 breast cancer cases (median age at diagnosis: 40 years, range 22–67) and 38 had ovarian cancer (median age at diagnosis: 52.5 years, range 26–79). Of genotyped cases, 18 (10%) carried one of 12 pathogenic or likely-pathogenic variants, 12 in BRCA1, 6 in BRCA2. Only one was a rearrangement. Three variants recurred in more than one case; one was detected in five seemingly unrelated families. The detection rate for all breast cancer cases was 4%, 5% in bilateral breast cancer cases and 3% if breast cancer was diagnosed < 40 years. Of patients with ovarian cancer, 12/38 (32%) were carriers; the detection rate reached 75% (3/4) among patients diagnosed with both breast and ovarian cancer.

Conclusions

The overall yield of comprehensive BRCA1/2 testing in high-risk Israeli Arab individuals is low in breast cancer patients, and much higher in ovarian cancer patients. These results may guide optimal cancer susceptibility testing strategy in the Arab–Israeli population.

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References

  1. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 62:676–689

    Article  CAS  Google Scholar 

  2. Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S et al (2017) NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J Natl Compr Canc Netw 15:9–20

    Article  CAS  Google Scholar 

  3. Karami F, Mehdipour P (2013) A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. Biomed Res Int 2013:928562. https://doi.org/10.1155/2013/928562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. The Central Bureau of Statistics. https://www.cbs.gov.il/en/subjects/Pages/Population.aspx. Accessed 16 Mar 2019

  5. Spencer C. Tucker; Priscilla Roberts (12 May 2008). The Encyclopedia of the Arab-Israeli Conflict: A Political, Social, and Military History [4 volumes]: A Political, Social, and Military History. ABC-CLIO. p. 503. ISBN 978-1-85109-842-2

  6. Al-Kuraya K, Schraml P, Sheikh S, Amr S, Torhorst J, Tapia C et al (2005) Predominance of high-grade pathway in breast cancer development of Middle East women. Mod Pathol 18:891–897

    Article  Google Scholar 

  7. Atoum MF, Al-Hourani HM (2004) Lifestyle related risk factors for breast cancer in Jordanian females. Saudi Med J 25:1245–1248

    PubMed  Google Scholar 

  8. CI5 - Home [Internet]. Cancer Incid. Five Cont. Vol X Electron. Version. http://ci5.iarc.fr/Default.aspx. Accessed 15 Oct 2018

  9. Bener A, Ayub H, Kakil R, Ibrahim W (2008) Patterns of cancer incidence among the population of qatar: a worldwide comparative study. Asian Pac J Cancer Prev 9:19–24

    PubMed  Google Scholar 

  10. El Saghir NS, Khalil MK, Eid T, El Kinge AR, Charafeddine M, Geara F et al (2007) Trends in epidemiology and management of breast cancer in developing Arab countries: a literature and registry analysis. Int J Surg 5:225–233

    Article  Google Scholar 

  11. Mahfoudh W, Bouaouina N, Ahmed SB, Gabbouj S, Shan J, Mathew R et al (2012) Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population. Mol Biol Rep 39:1037–1046

    Article  CAS  Google Scholar 

  12. Lolas Hamameh S, Renbaum P, Kamal L, Dweik D, Salahat M, Jaraysa T et al (2017) Genomic analysis of inherited breast cancer among Palestinian women: genetic heterogeneity and a founder mutation in TP53. Int J Cancer 141:750–756

    Article  CAS  Google Scholar 

  13. Laitman Y, Borsthein RT, Stoppa-Lyonnet D, Dagan E, Castera L, Goislard M et al (2011) Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat 127:489–495

    Article  Google Scholar 

  14. Zidan J, Zhou AY, van den Akker J, Laitman Y, Schayek H, Schnaider J et al (2017) Inherited predisposition to breast and ovarian cancer in non-Jewish populations in Israel. Breast Cancer Res Treat 166:881–885

    Article  CAS  Google Scholar 

  15. Parmigiani G, Berry D, Aguilar O (1998) Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145–158

    Article  CAS  Google Scholar 

  16. The Penn II Risk Model, BRCA 1 and BRCA 2 Mutation Predictor [Internet]. https://pennmodel2.pmacs.upenn.edu/penn2/index.jsp. Accessed 2 Sep 2017

  17. BRCA Calculator [Internet]. http://www.myriadpro.com/brca-risk-calculator/calc.html. Accessed 7 Sep 2017.

  18. Barnes-Kedar I, Bernstein-Molho R, Ginzach N, Hartmajer S, Shapira T, Magal N et al (2018) The yield of full BRCA1/2 genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations. Breast Cancer Res Treat 172:151–157

    Article  CAS  Google Scholar 

  19. Jalkh N, Nassar-Slaba J, Chouery E, Salem N, Uhrchammer N, Golmard L et al (2012) Prevalance of BRCA1 and BRCA2 mutations in familial breast cancer patients in Lebanon. Hered Cancer Clin Pract 10:7

    Article  CAS  Google Scholar 

  20. El Saghir NS, Zgheib NK, Assi HA, Khoury KE, Bidet Y, Jaber SM et al (2015) BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer. Oncologist 20:357–364

    Article  Google Scholar 

  21. Abdel-Razeq H, Al-Omari A, Zahran F, Arun B (2018) Germline BRCA1/BRCA2 mutations among high risk breast cancer patients in Jordan. BMC Cancer 18:152

    Article  Google Scholar 

  22. Cintolo-Gonzalez JA, Braun D, Blackford AL, Mazzola E, Acar A, Plichta JK et al (2017) Breast cancer risk models: a comprehensive overview of existing models, validation, and clinical applications. Breast Cancer Res Treat 164:263–284

    Article  Google Scholar 

  23. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H et al (2005) BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 104:2807–2816

    Article  CAS  Google Scholar 

  24. Franzese E, Centonze S, Diana A, Carlino F, Guerrera LP, Napoli MD et al (2019) PARP inhibitors in ovarian cancer. Cancer Treat Rev 73:1–9

    Article  CAS  Google Scholar 

  25. Menéndez M, Castellsagué J, Mirete M, Pros E, Feliubadaló L, Osorio A et al (2012) Assessing the RNA effect of 26 DNA variants in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 132:979–992

    Article  Google Scholar 

  26. Farra C, Dagher C, Badra R, Hammoud MS, Alameddine R, Awwad J et al (2019) BRCA mutation screening and patterns among high-risk Lebanese subjects. Hered Cancer Clin Pract 17:4. https://doi.org/10.1186/s13053-019-0105-9

    Article  PubMed  PubMed Central  Google Scholar 

  27. Quiles F, Teulé À, Martinussen Tandstad N, Feliubadaló L, Tornero E, del Valle J et al (2016) Identification of a founder BRCA1 mutation in the Moroccan population. Clin Genet 90:361–365

    Article  CAS  Google Scholar 

  28. Online Research Resources Developed at NHGRI [Internet]. Online Res. Resour. Dev. NHGRI. https://research.nhgri.nih.gov/. Accessed 15 Oct 2018

  29. Kadouri L, Bercovich D, Elimelech A, Lerer I, Sagi M, Glusman G et al (2007) A novel BRCA-1 mutation in Arab kindred from east Jerusalem with breast and ovarian cancer. BMC Cancer 7:14

    Article  Google Scholar 

  30. Paperna T, Sharon-Shwartzman N, Kurolap A, Goldberg Y, Moustafa N, Carasso Y et al (2019) Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype. J Med Genet. https://doi.org/10.1136/jmedgenet-2018-105824

    Article  PubMed  Google Scholar 

  31. Zick A, Kadouri L, Cohen S, Frohlinger M, Hamburger T, Zvi N et al (2017) Recurrent TP53 missense mutation in cancer patients of Arab descent. Fam Cancer 16:295–301

    Article  CAS  Google Scholar 

  32. Goldberg Y, Barnes-Kedar I, Lerer I, Halpern N, Plesser M, Hubert A et al (2015) Genetic features of Lynch syndrome in the Israeli population. Clin Genet 87:549–553

    Article  CAS  Google Scholar 

  33. Abu Freha N, Leibovici Weissman Y, Fich A, Barnes Kedar I, Halpern M, Sztarkier I et al (2018) Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel. Fam Cancer 17:79–86

    Article  CAS  Google Scholar 

  34. Baris HN, Barnes-Kedar I, Toledano H, Halpern M, Hershkovitz D, Lossos A et al (2016) Constitutional mismatch repair deficiency in Israel: high proportion of founder mutations in MMR genes and consanguinity. Pediatr Blood Cancer 63:418–427. https://doi.org/10.1002/pbc.25818

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Yael Goldberg.

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All authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the IRB in the participating institutions.

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As data were aggregative and anonymous no informed consent was required by the institutional IRB.

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Bernstein-Molho, R., Barnes-Kedar, I., Ludman, M.D. et al. The yield of full BRCA1/2 genotyping in Israeli Arab high-risk breast/ovarian cancer patients. Breast Cancer Res Treat 178, 231–237 (2019). https://doi.org/10.1007/s10549-019-05379-6

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  • DOI: https://doi.org/10.1007/s10549-019-05379-6

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