Genome-wide association analysis identifies three new breast cancer susceptibility loci.
Ghoussaini M., Fletcher O., Michailidou K., Turnbull C., Schmidt MK., Dicks E., Dennis J., Wang Q., Humphreys MK., Luccarini C., Baynes C., Conroy D., Maranian M., Ahmed S., Driver K., Johnson N., Orr N., dos Santos Silva I., Waisfisz Q., Meijers-Heijboer H., Uitterlinden AG., Rivadeneira F., Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON) None., Hall P., Czene K., Irwanto A., Liu J., Nevanlinna H., Aittomäki K., Blomqvist C., Meindl A., Schmutzler RK., Müller-Myhsok B., Lichtner P., Chang-Claude J., Hein R., Nickels S., Flesch-Janys D., Tsimiklis H., Makalic E., Schmidt D., Bui M., Hopper JL., Apicella C., Park DJ., Southey M., Hunter DJ., Chanock SJ., Broeks A., Verhoef S., Hogervorst FBL., Fasching PA., Lux MP., Beckmann MW., Ekici AB., Sawyer E., Tomlinson I., Kerin M., Marme F., Schneeweiss A., Sohn C., Burwinkel B., Guénel P., Truong T., Cordina-Duverger E., Menegaux F., Bojesen SE., Nordestgaard BG., Nielsen SF., Flyger H., Milne RL., Alonso MR., González-Neira A., Benítez J., Anton-Culver H., Ziogas A., Bernstein L., Dur CC., Brenner H., Müller H., Arndt V., Stegmaier C., Familial Breast Cancer Study (FBCS) None., Justenhoven C., Brauch H., Brüning T., Gene Environment Interaction of Breast Cancer in Germany (GENICA) Network None., Wang-Gohrke S., Eilber U., Dörk T., Schürmann P., Bremer M., Hillemanns P., Bogdanova NV., Antonenkova NN., Rogov YI., Karstens JH., Bermisheva M., Prokofieva D., Khusnutdinova E., Lindblom A., Margolin S., Mannermaa A., Kataja V., Kosma V-M., Hartikainen JM., Lambrechts D., Yesilyurt BT., Floris G., Leunen K., Manoukian S., Bonanni B., Fortuzzi S., Peterlongo P., Couch FJ., Wang X., Stevens K., Lee A., Giles GG., Baglietto L., Severi G., McLean C., Alnaes GG., Kristensen V., Børrensen-Dale A-L., John EM., Miron A., Winqvist R., Pylkäs K., Jukkola-Vuorinen A., Kauppila S., Andrulis IL., Glendon G., Mulligan AM., Devilee P., van Asperen CJ., Tollenaar RAEM., Seynaeve C., Figueroa JD., Garcia-Closas M., Brinton L., Lissowska J., Hooning MJ., Hollestelle A., Oldenburg RA., van den Ouweland AMW., Cox A., Reed MWR., Shah M., Jakubowska A., Lubinski J., Jaworska K., Durda K., Jones M., Schoemaker M., Ashworth A., Swerdlow A., Beesley J., Chen X., kConFab Investigators None., Australian Ovarian Cancer Study Group None., Muir KR., Lophatananon A., Rattanamongkongul S., Chaiwerawattana A., Kang D., Yoo K-Y., Noh D-Y., Shen C-Y., Yu J-C., Wu P-E., Hsiung C-N., Perkins A., Swann R., Velentzis L., Eccles DM., Tapper WJ., Gerty SM., Graham NJ., Ponder BAJ., Chenevix-Trench G., Pharoah PDP., Lathrop M., Dunning AM., Rahman N., Peto J., Easton DF.
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.