Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
Kuchenbaecker KB., Neuhausen SL., Robson M., Barrowdale D., McGuffog L., Mulligan AM., Andrulis IL., Spurdle AB., Schmidt MK., Schmutzler RK., Engel C., Wappenschmidt B., Nevanlinna H., Thomassen M., Southey M., Radice P., Ramus SJ., Domchek SM., Nathanson KL., Lee A., Healey S., Nussbaum RL., Rebbeck TR., Arun BK., James P., Karlan BY., Lester J., Cass I., Registry BCF., Terry MB., Daly MB., Goldgar DE., Buys SS., Janavicius R., Tihomirova L., Tung N., Dorfling CM., van Rensburg EJ., Steele L., v O Hansen T., Ejlertsen B., Gerdes A-M., Nielsen FC., Dennis J., Cunningham J., Hart S., Slager S., Osorio A., Benitez J., Duran M., Weitzel JN., Tafur I., Hander M., Peterlongo P., Manoukian S., Peissel B., Roversi G., Scuvera G., Bonanni B., Mariani P., Volorio S., Dolcetti R., Varesco L., Papi L., Tibiletti MG., Giannini G., Fostira F., Konstantopoulou I., Garber J., Hamann U., Donaldson A., Brewer C., Foo C., Evans DG., Frost D., Eccles D., Douglas F., Brady A., Cook J., Tischkowitz M., Adlard J., Barwell J., Ong K-R., Walker L., Izatt L., Side LE., Kennedy MJ., Rogers MT., Porteous ME., Morrison PJ., Platte R., Eeles R., Davidson R., Hodgson S., Ellis S., Godwin AK., Rhiem K., Meindl A., Ditsch N., Arnold N., Plendl H., Niederacher D., Sutter C., Steinemann D., Bogdanova-Markov N., Kast K., Varon-Mateeva R., Wang-Gohrke S., Gehrig A., Markiefka B., Buecher B., Lefol C., Stoppa-Lyonnet D., Rouleau E., Prieur F., Damiola F., Barjhoux L., Faivre L., Longy M., Sevenet N., Sinilnikova OM., Mazoyer S., Bonadona V., Caux-Moncoutier V., Isaacs C., Van Maerken T., Claes K., Piedmonte M., Andrews L., Hays J., Rodriguez GC., Caldes T., de la Hoya M., Khan S., Hogervorst FBL., Aalfs CM., de Lange JL., Meijers-Heijboer HEJ., van der Hout AH., Wijnen JT., van Roozendaal KEP., Mensenkamp AR., van den Ouweland AMW., van Deurzen CHM., van der Luijt RB., Olah E., Diez O., Lazaro C., Blanco I., Teulé A., Menendez M., Jakubowska A., Lubinski J., Cybulski C., Gronwald J., Jaworska-Bieniek K., Durda K., Arason A., Maugard C., Soucy P., Montagna M., Agata S., Teixeira MR., Olswold C., Lindor N., Pankratz VS., Hallberg E., Wang X., Szabo CI., Vijai J., Jacobs L., Corines M., Lincoln A., Berger A., Fink-Retter A., Singer CF., Rappaport C., Kaulich DG., Pfeiler G., Tea M-K., Phelan CM., Mai PL., Greene MH., Rennert G., Imyanitov EN., Glendon G., Toland AE., Bojesen A., Pedersen IS., Jensen UB., Caligo MA., Friedman E., Berger R., Laitman Y., Rantala J., Arver B., Loman N., Borg A., Ehrencrona H., Olopade OI., Simard J., Easton DF., Chenevix-Trench G., Offit K., Couch FJ., Antoniou AC.
Abstract Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.