Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Research output: Contribution to journalJournal articleResearchpeer-review

Roger L Milne, Karoline B Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K Bolla, Lesley McGuffog, Qin Wang, Cora M Aalfs, ABCTB Investigators, Marcia Adams, Julian Adlard & 27 others Simona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, Jamie Allen, Christine B Ambrosone, Christopher I Amos, Irene L Andrulis, Hoda Anton-Culver, Natalia N Antonenkova, Volker Arndt, Norbert Arnold, Kristan J Aronson, Bernd Auber, Paul L Auer, Margreet G E M Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Stig E Bojesen, Anne-Marie Gerdes, Anne-Vibeke Lænkholm, Børge G Nordestgaard, Marjanka K Schmidt, Antonis C Antoniou, Jacques Simard

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.

Original languageEnglish
JournalNature Genetics
Issue number12
Pages (from-to)1767-1778
Publication statusPublished - 2017

    Research areas

  • BRCA1 Protein/genetics, Breast Neoplasms/ethnology, European Continental Ancestry Group/genetics, Female, Genetic Predisposition to Disease/ethnology, Genome-Wide Association Study/methods, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Receptors, Estrogen/metabolism, Risk Factors

ID: 195042726