Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
Zhang H., Ahearn TU., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara TA., Zhao N., Bolla MK., Dunning AM., Dennis J., Wang Q., Ful ZA., Aittomäki K., Andrulis IL., Anton-Culver H., Arndt V., Aronson KJ., Arun BK., Auer PL., Azzollini J., Barrowdale D., Becher H., Beckmann MW., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova NV., Bojesen SE., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker SY., Brüning T., Burwinkel B., Buys SS., Byers H., Caldés T., Caligo MA., Calvello M., Campa D., Castelao JE., Chang-Claude J., Chanock SJ., Christiaens M., Christiansen H., Chung WK., Claes KBM., Clarke CL., Cornelissen S., Couch FJ., Cox A., Cross SS., Czene K., Daly MB., Devilee P., Diez O., Domchek SM., Dörk T., Dwek M., Eccles DM., Ekici AB., Evans DG., Fasching PA., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur SM., Garber J., García-Sáenz JA., Gaudet MM., Gayther SA., Giles GG., Godwin AK., Goldberg MS., Goldgar DE., González-Neira A., Greene MH., Gronwald J., Guénel P., Häberle L., Hahnen E., Haiman CA., Hake CR., Hall P., Hamann U., Harkness EF., Heemskerk-Gerritsen BAM., Hillemanns P., Hogervorst FBL., Holleczek B., Hollestelle A., Hooning MJ., Hoover RN., Hopper JL., Howell A., Huebner H., Hulick PJ., Imyanitov EN., kConFab Investigators ., ABCTB Investigators ., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John EM., Jones ME., Jung A., Kaaks R., Kapoor PM., Karlan BY., Keeman R., Khan S., Khusnutdinova E., Kitahara CM., Ko Y-D., Konstantopoulou I., Koppert LB., Koutros S., Kristensen VN., Laenkholm A-V., Lambrechts D., Larsson SC., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W-Y., Loud JT., Lubinski J., Lukomska A., MacInnis RJ., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez ME., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan AM., Mulot C., Muranen TA., Nathanson KL., Neuhausen SL., Nevanlinna H., Neven P., Newman WG., Nielsen FC., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade OI., Olsson H., Orr N., Papi L., Papp J., Park-Simon T-W., Parsons MT., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus SJ., Rantala J., Rashid MU., Rennert G., Rennert HS., Risch HA., Romero A., Rookus MA., Rübner M., Rüdiger T., Saloustros E., Sampson S., Sandler DP., Sawyer EJ., Scheuner MT., Schmutzler RK., Schneeweiss A., Schoemaker MJ., Schöttker B., Schürmann P., Senter L., Sharma P., Sherman ME., Shu X-O., Singer CF., Smichkoska S., Soucy P., Southey MC., Spinelli JJ., Stone J., Stoppa-Lyonnet D., EMBRACE Study ., GEMO Study Collaborators ., Swerdlow AJ., Szabo CI., Tamimi RM., Tapper WJ., Taylor JA., Teixeira MR., Terry M., Thomassen M., Thull DL., Tischkowitz M., Toland AE., Tollenaar RAEM., Tomlinson I., Torres D., Troester MA., Truong T., Tung N., Untch M., Vachon CM., van den Ouweland AMW., van der Kolk LE., van Veen EM., vanRensburg EJ., Vega A., Wappenschmidt B., Weinberg CR., Weitzel JN., Wildiers H., Winqvist R., Wolk A., Yang XR., Yannoukakos D., Zheng W., Zheng W., Zorn KK., Milne RL., Kraft P., Simard J., Pharoah PDP., Michailidou K., Antoniou AC., Schmidt MK., Chenevix-Trench G., Easton DF., Chatterjee N., García-Closas M.
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.