Skip to main content

Advertisement

SpringerLink
Log in

Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel

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

Abstract

We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study. Overall, 282 individuals participated in the study: 149 (53 %) of Ashkenazi descent, 80 (28 %) Jewish non-Ashkenazi descent, 22 (8 %) of mixed Ashkenazi/non-Ashkenazi origin, 21 (7 %) were non-Jewish Caucasians, and the remaining patients (n = 10–3.5 %) were of Christian Arabs/Druze/unknown ethnicity. For breast cancer patients (n = 165), the median (range) age at diagnosis was 46 (22–90) years and for ovarian cancer (n = 15) 54 (38–69) years. Overall, 30 cases (10.6 %) were found to carry a pathogenic actionable mutation in the tested genes: 10 BRCA1 (3 non-founder mutations), 9 BRCA2 (8 non-founder mutations), and one each in the RAD51C and CHEK2 genes. Furthermore, actionable mutations were detected in 9 more cases in 4 additional genes (MSH2, RET, MSH6, and APC). No pathogenic mutations were detected in the other genotyped genes. In this high-risk population, 10.6 % harbored an actionable pathogenic mutation, including non-founder mutations in BRCA1/2 and in additional cancer susceptibility genes, suggesting that high-risk families should be genotyped and be assigned a genotype-based cancer risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. 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 60:505–514

    PubMed  PubMed Central  CAS  Google Scholar 

  3. 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 78:148–151

    Article  PubMed  CAS  Google Scholar 

  4. 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 91:1241–1247

    Article  PubMed  CAS  Google Scholar 

  5. 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 64:963–970

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 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 39:611–614

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 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 68:7006–7014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 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 4:50–55

    Article  PubMed  Google Scholar 

  9. 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 63:272–274

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Hilbers FS, Vreeswijk MP, van Asperen CJ, Devilee P (2013) The impact of next generation sequencing on the analysis of breast cancer susceptibility: a role for extremely rare genetic variation? Clin Genet 84:407–414

    Article  PubMed  CAS  Google Scholar 

  11. Catucci I, Milgrom R, Kushnir A, Laitman Y, Paluch-Shimon S, Volorio S, Ficarazzi F, Bernard L, Radice P, Friedman E, Peterlongo P (2012) Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families. Fam Cancer 11:483–491

    Article  PubMed  CAS  Google Scholar 

  12. Kushnir A, Laitman Y, Shimon SP, Berger R, Friedman E (2012) Germline mutations in RAD51C in Jewish high cancer risk families. Breast Cancer Res Treat 136:869–874

    Article  PubMed  CAS  Google Scholar 

  13. Figer A, Kaplan A, Frydman M, Lev D, Paswell J, Papa MZ, Goldman B, Friedman E (2002) Germline mutations in the PTEN gene in Israeli patients with Bannayan-Riley-Ruvalcaba syndrome and women with familial breast cancer. Clin Genet 62:298–302

    Article  PubMed  CAS  Google Scholar 

  14. Kurian AW, Hare EE, Mills MA, Kingham KE, McPherson L, Whittemore AS, McGuire V, Ladabaum U, Kobayashi Y, Lincoln SE, Cargill M, Ford JM (2014) Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32:2001–2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Lincoln SE, Kobayashi Y, Anderson MJ, Yang S, Desmond AJ, Mills MA, Nilsen GB, Jacobs KB, Monzon FA, Kurian AW, Ford JM, Ellisen LW (2015) A Systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn 17:533–544

    Article  PubMed  Google Scholar 

  16. 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 

  17. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG, College American, American College of Medical Genetics and Genomics (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15:565–574

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tavtigian SV, Oefner PJ, Babikyan D et al (2009) Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet 85:427–446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Zhang B, Beeghly-Fadiel A, Long J, Zheng W (2011) Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 12:477–488

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Shen L, Yin ZH, Wan Y, Zhang Y, Li K, Zhou BS (2012) Association between ATM polymorphisms and cancer risk: a meta-analysis. Mol Biol Rep 39:5719–5725

    Article  PubMed  CAS  Google Scholar 

  21. Laitman Y, Simeonov M, Herskovitz L, Kushnir A, Shimon-Paluch S, Kaufman B, Zidan J, Friedman E (2012) Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel. Breast Cancer Res Treat 133:1153–1157

    Article  PubMed  CAS  Google Scholar 

  22. 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 127:489–495

    Article  PubMed  Google Scholar 

  23. Rosenthal E, Moyes K, Arnell C, Evans B, Wenstrup RJ (2015) Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry. Breast Cancer Res Treat 149:223–227. Erratum in: Breast Cancer Res Treat (2015) 151:233

  24. Petrucelli N, Mange S, Fulbright JL, Dohany L, Zakalik D, Duquette D (2015) To reflex or not: additional BRCA1/2 testing in Ashkenazi Jewish individuals without founder mutations. J Genet Couns 24:285–293

    Article  PubMed  Google Scholar 

  25. Pelttari LM, Heikkinen T, Thompson D, Kallioniemi A, Schleutker J, Holli K, Blomqvist C, Aittomäki K, Bützow R, Nevanlinna H (2011) RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet 20:3278–3288

    Article  PubMed  CAS  Google Scholar 

  26. Kuusisto KM, Bebel A, Vihinen M, Schleutker J, Sallinen SL (2011) Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res 13:R20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388

    Article  PubMed  CAS  Google Scholar 

  28. Zick A, Cohen S, Hamburger T, Goldberg Y, Zvi N, Sagi M, Peretz T (2015) A BRCA1 frameshift mutation in women of Kurdish Jewish Descent. Open Breast Cancer J. doi:10.2174/1876817220150529E001

    Google Scholar 

  29. NCCN guidelines. Genetic/familial high-risk assessment: Breast and ovarian. Version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed 11 Nov 2015

  30. Castéra L, Krieger S, Rousselin A, Legros A, Baumann JJ, Bruet O, Brault B, Fouillet R, Goardon N, Letac O, Baert-Desurmont S, Tinat J, Bera O, Dugast C, Berthet P, Polycarpe F, Layet V, Hardouin A, Frébourg T, Vaur D (2014) Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet 22:1305–1313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR (2015) Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 121:25–33

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Steve Lincoln from InVitae Corporation for his insightful comments. We thank the following clinicians for referring patients: V Libman (Assaf Harofe Medical Center); R Shtoyerman (Kaplan Medical Center), N Siegelmann-Danieli (Maccabi Healthcare Services); B Klein and E Reinstein (Meir Medical Center); N Levi, N Peled, and SM Stemmer (Rabin Medical Center); A Amit, M Ben Harush, K Drumea, R Epelbaum, and M Wollner (Rambam Health Care Campus); A Ben Yehuda, H Friedman, D Kelsen, G Lazer, S Liberman, O Rosengarten, and S Zukerman (Shaare Zedek Medical Center); K Levanon (Sheba Medical Center); N Ashkenazi, F Azem, Dalit Barel, P Kahn, O Merimsky, E Naparstek, S Pelles Avraham, and G Rozner (Sourasky Medical Center); J Zidan and S Mordechai (Ziv Medical Center).

Author information

Author notes

    Authors and Affiliations

    1. Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel

      Tamar Yablonski-Peretz, Luna Kadouri & Ayala Hubert

    2. The Oncology Institute Sheba Medical Center, Tel-Hashomer, Israel

      Shani Paluch-Shimon, Bella Kaufman & Talia Golan

    3. Teva Pharmaceuticals, Shoham, Israel

      Lior Soussan Gutman, Yulia Kaplan, Addie Dvir & Yafit Glasser

    4. Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel

      Inbal Barnes-Kedar

    5. Department of Oncology, Rambam Health Care Campus, Haifa, Israel

      Valeriya Semenisty

    6. Oncology Institute, Kaplan Medical Center, Rehovot, Israel

      Noa Efrat

    7. Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel

      Victoria Neiman

    8. The Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel

      Rachel Michaelson-Cohen

    9. The Institute of Gastroenterology, Sheba Medical Center, Tel-Hashomer, Israel

      Lior Katz

    10. The Genetics Institute, Assaf Harofe Medical Center, Zerifin, Israel

      Orit Reish

    11. Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

      Tamar Safra

    12. The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

      Yuval Yaron

    13. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

      Orit Reish, Yuval Yaron & Eitan Friedman

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

      Eitan Friedman

    Authors
    1. Tamar Yablonski-Peretz
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Shani Paluch-Shimon
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lior Soussan Gutman
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yulia Kaplan
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Addie Dvir
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Inbal Barnes-Kedar
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Luna Kadouri
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Valeriya Semenisty
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Noa Efrat
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Victoria Neiman
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Yafit Glasser
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Rachel Michaelson-Cohen
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Lior Katz
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Bella Kaufman
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Talia Golan
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Orit Reish
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Ayala Hubert
      View author publications

      You can also search for this author in PubMed Google Scholar

    18. Tamar Safra
      View author publications

      You can also search for this author in PubMed Google Scholar

    19. Yuval Yaron
      View author publications

      You can also search for this author in PubMed Google Scholar

    20. Eitan Friedman
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Eitan Friedman.

    Ethics declarations

    Conflict of interest

    LSG, YK, AD, and YG are Teva Pharmaceuticals employees. YY is a consultant to Oncotest Teva. EF is an ad hoc consultant to Oncotest Teva.

    Additional information

    Tamar Yablonski-Peretz and Shani Paluch-Shimon authors have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Yablonski-Peretz, T., Paluch-Shimon, S., Gutman, L.S. et al. Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel. Breast Cancer Res Treat 155, 133–138 (2016). https://doi.org/10.1007/s10549-015-3662-2

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10549-015-3662-2

    Keywords

    Search

    Navigation