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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

  • Author(s): Couch, FJ
  • Kuchenbaecker, KB
  • Michailidou, K
  • Mendoza-Fandino, GA
  • Nord, S
  • Lilyquist, J
  • Olswold, C
  • Hallberg, E
  • Agata, S
  • Ahsan, H
  • Aittomäki, K
  • Ambrosone, C
  • Andrulis, IL
  • Anton-Culver, H
  • Arndt, V
  • Arun, BK
  • Arver, B
  • Barile, M
  • Barkardottir, RB
  • Barrowdale, D
  • Beckmann, L
  • Beckmann, MW
  • Benitez, J
  • Blank, SV
  • Blomqvist, C
  • Bogdanova, NV
  • Bojesen, SE
  • Bolla, MK
  • Bonanni, B
  • Brauch, H
  • Brenner, H
  • Burwinkel, B
  • Buys, SS
  • Caldes, T
  • Caligo, MA
  • Canzian, F
  • Carpenter, J
  • Chang-Claude, J
  • Chanock, SJ
  • Chung, WK
  • Claes, KBM
  • Cox, A
  • Cross, SS
  • Cunningham, JM
  • Czene, K
  • Daly, MB
  • Damiola, F
  • Darabi, H
  • De La Hoya, M
  • Devilee, P
  • Diez, O
  • Ding, YC
  • Dolcetti, R
  • Domchek, SM
  • Dorfling, CM
  • Dos-Santos-Silva, I
  • Dumont, M
  • Dunning, AM
  • Eccles, DM
  • Ehrencrona, H
  • Ekici, AB
  • Eliassen, H
  • Ellis, S
  • Fasching, PA
  • Figueroa, J
  • Flesch-Janys, D
  • Försti, A
  • Fostira, F
  • Foulkes, WD
  • Friebel, T
  • Friedman, E
  • Frost, D
  • Gabrielson, M
  • Gammon, MD
  • Ganz, PA
  • Gapstur, SM
  • Garber, J
  • Gaudet, MM
  • Gayther, SA
  • Gerdes, AM
  • Ghoussaini, M
  • Giles, GG
  • Glendon, G
  • Godwin, AK
  • Goldberg, MS
  • Goldgar, DE
  • González-Neira, A
  • Greene, MH
  • Gronwald, J
  • Guénel, P
  • Gunter, M
  • Haeberle, L
  • Haiman, CA
  • et al.
Abstract

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10-8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

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