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

Roger L. Milne*, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindstrom, Shirley Hui, Audrey Lemacon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K. Bolla, Lesley McGuffog, Qin Wang, Cora M. Aalfs, Marcia Adams, Julian Adlard, Simona AgataShahana Ahmed, Habibul Ahsan, Kristiina Aittomaki, 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, Francois Bacot, Judith Balmana, Monica Barile, Laure Barjhoux, Rosa B. Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Marina Bermisheva, Jan C. Oosterwijk, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, KConFab AOCS Investigators, NBSC Collaborators

*Corresponding author for this work

Research output: Contribution to journalLetterAcademicpeer-review

110 Citations (Scopus)

Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). 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 x 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
Pages (from-to)1767-1778
Number of pages15
JournalNature Genetics
Volume49
Issue number12
DOIs
Publication statusPublished - Dec-2017

Keywords

  • GENOME-WIDE ASSOCIATION
  • BRCA2 MUTATION CARRIERS
  • SUSCEPTIBILITY LOCI
  • CONFER SUSCEPTIBILITY
  • FUNCTIONAL VARIANTS
  • OVARIAN CANCERS
  • COMMON VARIANTS
  • CONSORTIUM
  • EXPRESSION
  • DISEASE

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