BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.
Meeks HD., Song H., Michailidou K., Bolla MK., Dennis J., Wang Q., Barrowdale D., Frost D., EMBRACE None., McGuffog L., Ellis S., Feng B., Buys SS., Hopper JL., Southey MC., Tesoriero A., kConFab Investigators None., James PA., Bruinsma F., Campbell IG., Australia Ovarian Cancer Study Group None., Broeks A., Schmidt MK., Hogervorst FBL., HEBON None., 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 None., 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 None., 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 None., Antoniou AC., Berchuck A., Swerdlow A., Chenevix-Trench G., Dunning AM., Pharoah PDP., Hall P., Easton DF., Couch FJ., Spurdle AB., Goldgar DE.
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.