Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Engel C., Versmold B., Wappenschmidt B., Simard J., Easton DF., Peock S., Cook M., Oliver C., Frost D., Mayes R., Evans DG., Eeles R., Paterson J., Brewer C., Epidemiological Study of Familial Breast Cancer (EMBRACE) None., McGuffog L., Antoniou AC., Stoppa-Lyonnet D., Sinilnikova OM., Barjhoux L., Frenay M., Michel C., Leroux D., Dreyfus H., Toulas C., Gladieff L., Uhrhammer N., Bignon Y-J., Meindl A., Arnold N., Varon-Mateeva R., Niederacher D., Preisler-Adams S., Kast K., Deissler H., Sutter C., Gadzicki D., Chenevix-Trench G., Spurdle AB., Chen X., Beesley J., Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) None., Olsson H., Kristoffersson U., Ehrencrona H., Liljegren A., Swedish Breast Cancer Study, Sweden (SWE-BRCA) None., van der Luijt RB., van Os TA., van Leeuwen FE., Hereditary Breast and Ovarian cancer group Netherlands (HEBON) None., Domchek SM., Rebbeck TR., Nathanson KL., Osorio A., Ramón y Cajal T., Konstantopoulou I., Benítez J., Friedman E., Kaufman B., Laitman Y., Mai PL., Greene MH., Nevanlinna H., Aittomäki K., Szabo CI., Caldes T., Couch FJ., Andrulis IL., Godwin AK., Hamann U., Schmutzler RK., Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) None.
BackgroundThe genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.MethodsTo evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).ResultsThe minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.ConclusionsCASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.ImpactThe combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.