Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

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Broeks A, Schmidt MK, Sherman ME, Couch FJ, Hopper JL, Dite GS, Apicella C, Smith LD, Hammet F, Southey MC, Van 't Veer LJ, de Groot R, Smit VT, Fasching PA, Beckmann MW, Jud S, Ekici AB, Hartmann A, Hein A, Schulz-Wendtland R, Burwinkel B, Marme F, Schneeweiss A, Sinn HP, Sohn C, Tchatchou S, Bojesen SE, Nordestgaard BG, Flyger H, Orsted DD, Kaur-Knudsen D, Milne RL, Perez JI, Zamora P, Rodriguez PM, Benitez J, Brauch H, Justenhoven C, Ko YD, Hamann U, Fischer HP, Bruning T, Pesch B, Chang-Claude J, Wang-Gohrke S, Bremer M, Karstens JH, Hillemanns P, Dork T, Nevanlinna HA, Heikkinen T, Heikkila P, Blomqvist C, Aittomaki K, Aaltonen K, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kauppinen JM, Kataja V, Auvinen P, Eskelinen M, Soini Y, Chenevix-Trench G, Spurdle AB, Beesley J, Chen X, Holland H, Lambrechts D, Claes B, Vandorpe T, Neven P, Wildiers H, Flesch-Janys D, Hein R, Loning T, Kosel M, Fredericksen ZS, Wang X, Giles GG, Baglietto L, Severi G, McLean C, Haiman CA, Henderson BE, Le Marchand L, Kolonel LN, Alnaes GG, Kristensen V, Borresen-Dale AL, Hunter DJ, Hankinson SE, Andrulis IL, Mulligan AM, O'Malley FP, Devilee P, Huijts PE, Tollenaar RA, Van Asperen CJ, Seynaeve CS, Chanock SJ, Lissowska J, Brinton L, Peplonska B, Figueroa J, Yang XR, Hooning MJ, Hollestelle A, Oldenburg RA, Jager A, Kriege M, Ozturk B, van Leenders GJ, Hall P, Czene K, Humphreys K, Liu J, Cox A, Connley D, Cramp HE, Cross SS, Balasubramanian SP, Reed MW, Dunning AM, Easton DF, Humphreys MK, Caldas C, Blows F, Driver K, Provenzano E, Lubinski J, Jakubowska A, Huzarski T, Byrski T, Cybulski C, Gorski B, Gronwald J, Brennan P, Sangrajrang S, Gaborieau V, Shen CY, Hsiung CN, Yu JC, Chen ST, Hsu GC, Hou MF, Huang CS, Anton-Culver H, Ziogas A, Pharoah PD, Garcia-Closas M (2011) Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20:3289-3303


Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P

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