Abstract
BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7–92.8 years). Of these true negatives, 20 women (6.51–2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 –60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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):1117–1130
Antoniou AC, Pharoah PD, Easton DF, Evans DG (2006) BRCA1 and BRCA2 cancer risks. J Clin Oncol 24(20):3312–3313
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):2774–3770
Smith A, Moran A, Boyd MC, Bulman M, Shenton A, Smith L, Iddenden R, Woodward ER, Lalloo F, Maher ER, Evans DG (2007) Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 44(1):10–15
Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 25(43):5832–5836
Levy-Lahad E, Friedman E (2007) Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer 96(1):11–15
Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358(26):2796–2803
Jakubowska A, Jaworska K, Cybulski C, Janicka A, Szymańska-Pasternak J, Lener M, Narod SA, Lubiński J, IHCC-Breast Cancer Study Group (2009) Do BRCA1 modifiers also affect the risk of breast cancer in non-carriers? Eur J Cancer 45(5):837–842
Gronwald J, Cybulski C, Lubinski J, Narod SA (2007) Phenocopies in breast cancer 1 (BRCA1) families: implications for genetic counselling. J Med Genet 44(4):e76
Goldgar D, Venne V, Conner T, Buys S (2007) BRCA phenocopies or ascertainment bias? Med Genet 44(8):e86
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
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 16(6):491–501
Rohlfs 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(1):24–29
Breslow NE, Day NE (1987) Statistical methods in cancer research. IARC Workshop 25–27 May 1983. IARC Sci Publ 82:1–406
Rowan E, Poll A, Narod SA (2007) A prospective study of breast cancer risk in relatives of BRCA1/BRCA2 mutation carriers. J Med Genet 44(8):e89
Acknowledgments
This study was sponsored by a grant from the Israel cancer association to the Israeli inherited breast cancer consortium. The Israel Cancer Association, a non-profit organization, sponsored a supplementary salary to Shiri Bernholtz. All other co-authors declare that they have no financial ties with the Israel Cancer Association, the organization that sponsored the research.
Conflict of interest
All authors declare that they have no conflict of interest regarding the data published herein.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bernholtz, S., Laitman, Y., Kaufman, B. et al. Phenocopy breast cancer rates in Israeli BRCA1 BRCA2 mutation carrier families: is the risk increased in non-carriers?. Breast Cancer Res Treat 132, 669–673 (2012). https://doi.org/10.1007/s10549-011-1886-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-011-1886-3