BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

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BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

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  • Meeks, HD; Song, H; Michailidou, K; Bolla, MK; Dennis, J; Wang, Q; Barrowdale, D; Frost, D; EMBRACE, ; McGuffog, L; Ellis, S; Feng, B; Buys, SS; Hopper, JL; Southey, MC; Tesoriero, A; kConFab Investigators, ; James, PA; Bruinsma, F; Campbell, IG; Australia Ovarian Cancer Study Group, ; Broeks, A; Schmidt, MK; Hogervorst, FBL; HEBON, ; Beckman, MW; Fasching, PA; Fletcher, O; Johnson, N; Sawyer, EJ; Riboli, E; Banerjee, S; Menon, U; Tomlinson, I; Burwinkel, B; Hamann, U; Marme, F; Rudolph, A; Janavicius, R; Tihomirova, L; Tung, N; Garber, J; Cramer, D; Terry, KL; Poole, EM; Tworoger, SS; Dorfling, CM; van Rensburg, EJ; Godwin, AK; Guénel, P; Truong, T; GEMO Study Collaborators, ; Stoppa-Lyonnet, D; Damiola, F; Mazoyer, S; Sinilnikova, OM; Isaacs, C; Maugard, C; Bojesen, SE; Flyger, H; Gerdes, A-M; Hansen, TVO; Jensen, A; Kjaer, SK; Hogdall, C; Hogdall, E; Pedersen, IS; Thomassen, M; Benitez, J; González-Neira, A; Osorio, A; Hoya, MDL; Segura, PP; Diez, O; Lazaro, C; Brunet, J; Anton-Culver, H; Eunjung, L; John, EM; Neuhausen, SL; Ding, YC; Castillo, D; Weitzel, JN; Ganz, PA; Nussbaum, RL; Chan, SB; Karlan, BY; Lester, J; Wu, A; Gayther, S; Ramus, SJ; Sieh, W; Whittermore, AS; Monteiro, ANA; Phelan, CM; Terry, MB; Piedmonte, M; Offit, K; Robson, M; Levine, D; Moysich, KB; Cannioto, R; Olson, SH; Daly, MB; Nathanson, KL; Domchek, SM; Lu, KH; Liang, D; Hildebrant, MAT; Ness, R; Modugno, F; Pearce, L; Goodman, MT; Thompson, PJ; Brenner, H; Butterbach, K; Meindl, A; Hahnen, E; Wappenschmidt, B; Brauch, H; Brüning, T; Blomqvist, C; Khan, S; Nevanlinna, H; Pelttari, LM; Aittomäki, K; Butzow, R; Bogdanova, NV; Dörk, T; Lindblom, A; Margolin, S; Rantala, J; Kosma, V-M; Mannermaa, A; Lambrechts, D; Neven, P; Claes, KBM; Maerken, TV; Chang-Claude, J; Flesch-Janys, D; Heitz, F; Varon-Mateeva, R; Peterlongo, P; Radice, P; Viel, A; Barile, M; Peissel, B; Manoukian, S; Montagna, M; Oliani, C; Peixoto, A; Teixeira, MR; Collavoli, A; Hallberg, E; Olson, JE; Goode, EL; Hart, SN; Shimelis, H; Cunningham, JM; Giles, GG; Milne, RL; Healey, S; Tucker, K; Haiman, CA; Henderson, BE; Goldberg, MS; Tischkowitz, M; Simard, J; Soucy, P; Eccles, DM; Le, N; Borresen-Dale, A-L; Kristensen, V; Salvesen, HB; Bjorge, L; Bandera, EV; Risch, H; Zheng, W; Beeghly-Fadiel, A; Cai, H; Pylkäs, K; Tollenaar, RAEM; Ouweland, AMWVD; Andrulis, IL; Knight, JA; OCGN, ; Narod, S; Devilee, P; Winqvist, R; Figueroa, J; Greene, MH; Mai, PL; Loud, JT; García-Closas, M; Schoemaker, MJ; Czene, K; Darabi, H; McNeish, I; Siddiquil, N; Glasspool, R; Kwong, A; Park, SK; Teo, SH; Yoon, S-Y; Matsuo, K; Hosono, S; Woo, YL; Gao, Y-T; Foretova, L; Singer, CF; Rappaport-Feurhauser, C; Friedman, E; Laitman, Y; Rennert, G; Imyanitov, EN; Hulick, PJ; Olopade, OI; Senter, L; Olah, E; Doherty, JA; Schildkraut, J; Koppert, LB; Kiemeney, LA; Massuger, LFAG; Cook, LS; Pejovic, T; Li, J; Borg, A; Öfverholm, A; Rossing, MA; Wentzensen, N; Henriksson, K; Cox, A; Cross, SS; Pasini, BJ; Shah, M; Kabisch, M; Torres, D; Jakubowska, A; Lubinski, J; Gronwald, J; Agnarsson, BA; Kupryjanczyk, J; Moes-Sosnowska, J; Fostira, F; Konstantopoulou, I; Slager, S; Jones, M; PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, ; Antoniou, AC; Berchuck, A; Swerdlow, A; Chenevix-Trench, G; Dunning, AM; Pharoah, PDP; Hall, P; Easton, DF; Couch, FJ; Spurdle, AB; Goldgar, DE

Published Date

  • February 2016

Published In

Volume / Issue

  • 108 / 2

PubMed ID

  • 26586665

Pubmed Central ID

  • 26586665

Electronic International Standard Serial Number (EISSN)

  • 1460-2105

Digital Object Identifier (DOI)

  • 10.1093/jnci/djv315

Language

  • eng

Conference Location

  • United States