Advertisement

Cancer risk in Jewish BRCA1 and BRCA2 mutation carriers: Effects of oral contraceptive use and parental origin of mutation

  • Shiri Bernholtz
  • Yael Laitman
  • Bella Kaufman
  • Shani Paluch Shimon
  • Eitan FriedmanEmail author
Epidemiology

Abstract

BRCA1 and BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. The effects of oral contraceptives (OC) on breast cancer risk in mutation carriers are unclear, and the putative effect of parental origin of mutation on cancer risk has not been reported. Data on OC use and parental origin of the mutation were obtained at counseling from 888 BRCA1 (n = 638) or BRCA2 (n = 250) Jewish Israeli mutation carriers who were counseled and genotyped in a single medical center. Overall, 403 (45.4%) of participants had breast cancer (age at diagnosis 49.65 ± 12.2 years), 112 (12.6%) ovarian cancer (age at diagnosis 56.8 ± 10.8 years) and the rest (n = 373−42%) were asymptomatic carriers (age at counseling 40.7 ± 10.6 years). Of study participants, 472 (53.15%) ever used OC, and 298 used OC for at least 5 years. In 129 the mutation originated on the paternal side as judged by direct testing or obligate carriership and in 460 the mutation was maternally inherited. Multivariate logistic regression analysis, and stratifying for birth year, age at menarche, breast feeding, and number of births, showed that ever use of OC (Hazards Ratio-HR = 1.84 95% CI 1.465–2.314, P = 0.001) and paternal compared with maternal origin of mutation (OR = 1.55 95% CI 1.14–2.12, P = 0.006) were significantly associated with breast cancer and an earlier age at breast cancer diagnosis. The authors conclude that OC use and paternal origin of mutation affect breast cancer penetrance in Jewish BRCA1 and BRCA2 mutation carriers.

Keywords

Breast cancer BRCA1/BRCA2 germline mutations OC use Parental origin of mutation 

Notes

Acknowledgments

This study was performed in partial fulfillment of the requirements for graduation of Shiri Bernholtz, from Ort Braude, Karmiel, Israel. This study was sponsored by a grant from the Israel cancer association to the Israeli inherited breast cancer consortium.

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300PubMedCrossRefGoogle Scholar
  2. 2.
    Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M (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 62:676–689PubMedCrossRefGoogle Scholar
  3. 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 60:505–514PubMedGoogle Scholar
  4. 4.
    Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020PubMedGoogle Scholar
  5. 5.
    Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130PubMedCrossRefGoogle Scholar
  6. 6.
    Simchoni S, Friedman E, Kaufman B, Gershoni-Baruch R, Orr-Urtreger A, Kedar-Barnes I, Shiri-Sverdlov R, Dagan E, Tsabari S, Shohat M, Catane R, King MC, Lahad A, Levy-Lahad E (2006) Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci USA 103(10):3770–3774PubMedCrossRefGoogle Scholar
  7. 7.
    Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 25(43):5832–5836PubMedCrossRefGoogle Scholar
  8. 8.
    Levy-Lahad E, Friedman E (2007) Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer 96(1):11–15PubMedCrossRefGoogle Scholar
  9. 9.
    Collaborative Group on Hormonal Factors in Breast Cancer (1996) Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 347(9017):1713–1727CrossRefGoogle Scholar
  10. 10.
    Grabrick DM, Hartmann LC, Cerhan JR, Vierkant RA, Therneau TM, Vachon CM, Olson JE, Couch FJ, Anderson KE, Pankratz VS, Sellers TA (2000) Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 284:1791–1798PubMedCrossRefGoogle Scholar
  11. 11.
    Ursin G, Henderson BE, Haile RW, Pike MC, Zhou N, Diep A, Bernstein L (1997) Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57:3678–3681PubMedGoogle Scholar
  12. 12.
    Narod SA (2001) Hormonal prevention of hereditary breast cancer. Ann NY Acad Sci 952:36–43PubMedCrossRefGoogle Scholar
  13. 13.
    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 analysis of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast cancer. Hum Mutat 6:491–501CrossRefGoogle Scholar
  14. 14.
    Rohlf EM, Learning WG, Friedman KJ, Couch FJ, Weber BL, Silverman LM (1997) Direct detection of mutations in the breast and ovarian cancer susceptibility gene BRCA1 by PCR–mediated site-directed mutagenesis. Clin Chem 43:24–29Google Scholar
  15. 15.
    Schüler A, Weber S, Neuhäuser M, Jurklies C, Lehnert T, Heimann H, Rudolph G, Jöckel KH, Bornfeld N, Lohmann DR (2005) Age at diagnosis of isolated unilateral retinoblastoma does not distinguish patients with and without a constitutional RB1 gene mutation but is influenced by a parent-of-origin effect. Eur J Cance 41(5):735–740CrossRefGoogle Scholar
  16. 16.
    Morison IM, Ellis LM, Teague LR, Reeve AE (2002) Preferential loss of maternal 9p alleles in childhood acute lymphoblastic leukemia. Blood 99(1):375–377PubMedCrossRefGoogle Scholar
  17. 17.
    Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella J, Davis K, Stavrou D, MacCollin M (2000) The parental origin of new mutations in neurofibromatosis 2. Neurogenetics 3(1):17–24PubMedCrossRefGoogle Scholar
  18. 18.
    Aretz S, Uhlhaas S, Caspari R, Mangold E, Pagenstecher C, Propping P, Friedl W (2004) Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur J Hum Genet 12(1):52–58PubMedCrossRefGoogle Scholar
  19. 19.
    Mantovani G, Bondioni S, Lania AG, Corbetta S, de Sanctis L, Cappa M, Di Battista E, Chanson P, Beck-Peccoz P, Spada A (2004) Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab 89(6):3007–3009PubMedCrossRefGoogle Scholar
  20. 20.
    Merajver SD, Frank TS, Xu J, Pham TM, Calzone KA, Bennett-Baker P, Chamberlain J, Boyd J, Garber JE, Collins FS (1995) Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer. Clin Cancer Res 1(5):539–544PubMedGoogle Scholar
  21. 21.
    La Vecchia C, Altieri A, Franceschi S, Tavani A (2001) Oral contraceptives and cancer: an update. Drug Saf 24:741–754PubMedCrossRefGoogle Scholar
  22. 22.
    Gaffield ME, Culwell KR, Ravi A (2009) Oral contraceptives and family history of breast cancer. Contraception 80(4):372–380PubMedCrossRefGoogle Scholar
  23. 23.
    Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, Zikan M, Dusek L (2010) Hormonal contraception and risk of cancer. Hum Reprod Update 16(6):631–650PubMedCrossRefGoogle Scholar
  24. 24.
    Pasanisi P, Hédelin G, Berrino J, Chang-Claude J, Hermann S, Steel M, Haites N, Hart J, Peled R, Gafà L, Leggio L, Traina A, Amodio R, Primic-Zakelj M, Zadnik V, Veidebaum T, Tekkel M, Berrino F (2009) Oral contraceptive use and BRCA penetrance: a case-only study. Cancer Epidemiol Biomarkers Prev 18(7):2107–2113PubMedCrossRefGoogle Scholar
  25. 25.
    Jernström H, Loman N, Johannsson OT, Borg A, Olsson H (2005) Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing. Eur J Cancer 41(15):2312–2320PubMedCrossRefGoogle Scholar
  26. 26.
    Ursin G, Ross RK, Sullivan-Halley J, Hanisch R, Henderson B, Bernstein L (1998) Use of oral contraceptives and risk of breast cancer in young women. Breast Cancer Res Treat 50:175–184PubMedCrossRefGoogle Scholar
  27. 27.
    Heimdal K, Skovlund E, Moller P (2002) Oral contraceptives and risk of familial breast cancer. Cancer Detect Prev 26:23–27PubMedCrossRefGoogle Scholar
  28. 28.
    Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, Spirtas R, Weiss LK (2002) Oral contraceptives and the risk of breast cancer. N Engl J Med 346:2025–2032PubMedCrossRefGoogle Scholar
  29. 29.
    Kaduri L, Gibs M, Hubert A, Sagi M, Heching N, Lerer I, Uziely B, Weinberg N, Abeliovich D, Peretz T (1999) Genetic testing of breast and ovarian cancer patients: clinical characteristics and hormonal risk modifiers. Eur J Obstet Gynecol Reprod Biol 85:75–80PubMedCrossRefGoogle Scholar
  30. 30.
    Narod SA, Dubé MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, Provencher D, Heimdal K, Moller P, Robson M, Offit K, Isaacs C, Weber B, Friedman E, Gershoni-Baruch R, Rennert G, Pasini B, Wagner T, Daly M, Garber JE, Neuhausen SL, Ainsworth P, Olsson H, Evans G, Osborne M, Couch F, Foulkes WD, Warner E, Kim-Sing C, Olopade O, Tung N, Saal HM, Weitzel J, Merajver S, Gauthier-Villars M, Jernstrom H, Sun P, Brunet JS (2002) Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94:1773–1779PubMedGoogle Scholar
  31. 31.
    Thompson D, Easton D, Breast Cancer Linkage Consortium (2001) Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68(2):410–419PubMedCrossRefGoogle Scholar
  32. 32.
    Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68(3):700–710PubMedCrossRefGoogle Scholar
  33. 33.
    Lubinski J, Phelan CM, Ghadirian P, Lynch HT, Garber J, Weber B, Tung N, Horsman D, Isaacs C, Monteiro AN, Sun P, Narod SA (2004) Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer 23(1):1–10Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Shiri Bernholtz
    • 1
  • Yael Laitman
    • 1
  • Bella Kaufman
    • 2
    • 3
  • Shani Paluch Shimon
    • 2
  • Eitan Friedman
    • 1
    • 3
    Email author
  1. 1.Susanne-Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of GeneticsChaim Sheba Medical CenterTel-HashomerIsrael
  2. 2.Institute of OncologyChaim Sheba Medical CenterTel-HashomerIsrael
  3. 3.The Sackler School of MedicineTel-Aviv UniversityRamat AvivIsrael

Personalised recommendations