Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
Milne RL., Kuchenbaecker KB., Michailidou K., Beesley J., Kar S., Lindström S., Hui S., Lemaçon A., Soucy P., Dennis J., Jiang X., Rostamianfar A., Finucane H., Bolla MK., McGuffog L., Wang Q., Aalfs CM., ABCTB Investigators None., Adams M., Adlard J., Agata S., Ahmed S., Ahsan H., Aittomäki K., Al-Ejeh F., Allen J., Ambrosone CB., Amos CI., Andrulis IL., Anton-Culver H., Antonenkova NN., Arndt V., Arnold N., Aronson KJ., Auber B., Auer PL., Ausems MGEM., Azzollini J., Bacot F., Balmaña J., Barile M., Barjhoux L., Barkardottir RB., Barrdahl M., Barnes D., Barrowdale D., Baynes C., Beckmann MW., Benitez J., Bermisheva M., Bernstein L., Bignon Y-J., Blazer KR., Blok MJ., Blomqvist C., Blot W., Bobolis K., Boeckx B., Bogdanova NV., Bojesen A., Bojesen SE., Bonanni B., Børresen-Dale A-L., Bozsik A., Bradbury AR., Brand JS., Brauch H., Brenner H., Bressac-de Paillerets B., Brewer C., Brinton L., Broberg P., Brooks-Wilson A., Brunet J., Brüning T., Burwinkel B., Buys SS., Byun J., Cai Q., Caldés T., Caligo MA., Campbell I., Canzian F., Caron O., Carracedo A., Carter BD., Castelao JE., Castera L., Caux-Moncoutier V., Chan SB., Chang-Claude J., Chanock SJ., Chen X., Cheng T-YD., Chiquette J., Christiansen H., Claes KBM., Clarke CL., Conner T., Conroy DM., Cook J., Cordina-Duverger E., Cornelissen S., Coupier I., Cox A., Cox DG., Cross SS., Cuk K., Cunningham JM., Czene K., Daly MB., Damiola F., Darabi H., Davidson R., De Leeneer K., Devilee P., Dicks E., Diez O., Ding YC., Ditsch N., Doheny KF., Domchek SM., Dorfling CM., Dörk T., Dos-Santos-Silva I., Dubois S., Dugué P-A., Dumont M., Dunning AM., Durcan L., Dwek M., Dworniczak B., Eccles D., Eeles R., Ehrencrona H., Eilber U., Ejlertsen B., Ekici AB., Eliassen AH., EMBRACE None., Engel C., Eriksson M., Fachal L., Faivre L., Fasching PA., Faust U., Figueroa J., Flesch-Janys D., Fletcher O., Flyger H., Foulkes WD., Friedman E., Fritschi L., Frost D., Gabrielson M., Gaddam P., Gammon MD., Ganz PA., Gapstur SM., Garber J., Garcia-Barberan V., García-Sáenz JA., Gaudet MM., Gauthier-Villars M., Gehrig A., GEMO Study Collaborators None., Georgoulias V., Gerdes A-M., Giles GG., Glendon G., Godwin AK., Goldberg MS., Goldgar DE., González-Neira A., Goodfellow P., Greene MH., Alnæs GIG., Grip M., Gronwald J., Grundy A., Gschwantler-Kaulich D., Guénel P., Guo Q., Haeberle L., Hahnen E., Haiman CA., Håkansson N., Hallberg E., Hamann U., Hamel N., Hankinson S., Hansen TVO., Harrington P., Hart SN., Hartikainen JM., Healey CS., HEBON None., Hein A., Helbig S., Henderson A., Heyworth J., Hicks B., Hillemanns P., Hodgson S., Hogervorst FB., Hollestelle A., Hooning MJ., Hoover B., Hopper JL., Hu C., Huang G., Hulick PJ., Humphreys K., Hunter DJ., Imyanitov EN., Isaacs C., Iwasaki M., Izatt L., Jakubowska A., James P., Janavicius R., Janni W., Jensen UB., John EM., Johnson N., Jones K., Jones M., Jukkola-Vuorinen A., Kaaks R., Kabisch M., Kaczmarek K., Kang D., Kast K., kConFab/AOCS Investigators None., Keeman R., Kerin MJ., Kets CM., Keupers M., Khan S., Khusnutdinova E., Kiiski JI., Kim S-W., Knight JA., Konstantopoulou I., Kosma V-M., Kristensen VN., Kruse TA., Kwong A., Lænkholm A-V., Laitman Y., Lalloo F., Lambrechts D., Landsman K., Lasset C., Lazaro C., Le Marchand L., Lecarpentier J., Lee A., Lee E., Lee JW., Lee MH., Lejbkowicz F., Lesueur F., Li J., Lilyquist J., Lincoln A., Lindblom A., Lissowska J., Lo W-Y., Loibl S., Long J., Loud JT., Lubinski J., Luccarini C., Lush M., MacInnis RJ., Maishman T., Makalic E., Kostovska IM., Malone KE., Manoukian S., Manson JE., Margolin S., Martens JWM., Martinez ME., Matsuo K., Mavroudis D., Mazoyer S., McLean C., Meijers-Heijboer H., Menéndez P., Meyer J., Miao H., Miller A., Miller N., Mitchell G., Montagna M., Muir K., Mulligan AM., Mulot C., Nadesan S., Nathanson KL., NBSC Collaborators None., Neuhausen SL., Nevanlinna H., Nevelsteen I., Niederacher D., Nielsen SF., Nordestgaard BG., Norman A., Nussbaum RL., Olah E., Olopade OI., Olson JE., Olswold C., Ong K-R., Oosterwijk JC., Orr N., Osorio A., Pankratz VS., Papi L., Park-Simon T-W., Paulsson-Karlsson Y., Lloyd R., Pedersen IS., Peissel B., Peixoto A., Perez JIA., Peterlongo P., Peto J., Pfeiler G., Phelan CM., Pinchev M., Plaseska-Karanfilska D., Poppe B., Porteous ME., Prentice R., Presneau N., Prokofieva D., Pugh E., Pujana MA., Pylkäs K., Rack B., Radice P., Rahman N., Rantala J., Rappaport-Fuerhauser C., Rennert G., Rennert HS., Rhenius V., Rhiem K., Richardson A., Rodriguez GC., Romero A., Romm J., Rookus MA., Rudolph A., Ruediger T., Saloustros E., Sanders J., Sandler DP., Sangrajrang S., Sawyer EJ., Schmidt DF., Schoemaker MJ., Schumacher F., Schürmann P., Schwentner L., Scott C., Scott RJ., Seal S., Senter L., Seynaeve C., Shah M., Sharma P., Shen C-Y., Sheng X., Shimelis H., Shrubsole MJ., Shu X-O., Side LE., Singer CF., Sohn C., Southey MC., Spinelli JJ., Spurdle AB., Stegmaier C., Stoppa-Lyonnet D., Sukiennicki G., Surowy H., Sutter C., Swerdlow A., Szabo CI., Tamimi RM., Tan YY., Taylor JA., Tejada M-I., Tengström M., Teo SH., Terry MB., Tessier DC., Teulé A., Thöne K., Thull DL., Tibiletti MG., Tihomirova L., Tischkowitz M., Toland AE., Tollenaar RAEM., Tomlinson I., Tong L., Torres D., Tranchant M., Truong T., Tucker K., Tung N., Tyrer J., Ulmer H-U., Vachon C., van Asperen CJ., Van Den Berg D., van den Ouweland AMW., van Rensburg EJ., Varesco L., Varon-Mateeva R., Vega A., Viel A., Vijai J., Vincent D., Vollenweider J., Walker L., Wang Z., Wang-Gohrke S., Wappenschmidt B., Weinberg CR., Weitzel JN., Wendt C., Wesseling J., Whittemore AS., Wijnen JT., Willett W., Winqvist R., Wolk A., Wu AH., Xia L., Yang XR., Yannoukakos D., Zaffaroni D., Zheng W., Zhu B., Ziogas A., Ziv E., Zorn KK., Gago-Dominguez M., Mannermaa A., Olsson H., Teixeira MR., Stone J., Offit K., Ottini L., Park SK., Thomassen M., Hall P., Meindl A., Schmutzler RK., Droit A., Bader GD., Pharoah PDP., Couch FJ., Easton DF., Kraft P., Chenevix-Trench G., García-Closas M., Schmidt MK., Antoniou AC., Simard J.
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.