Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Research output: Contribution to journalArticle

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Details

Authors
  • Karoline B Kuchenbaecker
  • Susan J Ramus
  • Jonathan Tyrer
  • Andrew Lee
  • Howard C Shen
  • Jonathan Beesley
  • Kate Lawrenson
  • Lesley McGuffog
  • Sue Healey
  • Janet M Lee
  • Tassja J Spindler
  • Yvonne G Lin
  • Tanja Pejovic
  • Yukie Bean
  • Qiyuan Li
  • Simon Coetzee
  • Dennis Hazelett
  • Alexander Miron
  • Melissa Southey
  • Mary Beth Terry
  • David E Goldgar
  • Saundra S Buys
  • Ramunas Janavicius
  • Cecilia M Dorfling
  • Elizabeth J van Rensburg
  • Susan L Neuhausen
  • Yuan Chun Ding
  • Thomas V O Hansen
  • Lars Jønson
  • Anne-Marie Gerdes
  • Bent Ejlertsen
  • Daniel Barrowdale
  • Joe Dennis
  • Javier Benitez
  • Ana Osorio
  • Maria Jose Garcia
  • Ian Komenaka
  • Jeffrey N Weitzel
  • Pamela Ganschow
  • Paolo Peterlongo
  • Loris Bernard
  • Alessandra Viel
  • Bernardo Bonanni
  • Bernard Peissel
  • Siranoush Manoukian
  • Paolo Radice
  • Laura Papi
  • Laura Ottini
  • Maria Soller
  • Marie Stenmark-Askmalm
  • EMBRACE
Organisations
External organisations
  • Case Western Reserve University
  • University of Melbourne
  • Columbia University
  • University of Utah
  • Vilnius University Hospital
  • University of Pretoria
  • Beckman Research Institute of City of Hope
  • Spanish National Cancer Research Center (CNIO)
  • City of Hope Clinical Cancer Genetics Community Research Network
  • IFOM - The FIRC Institute of Molecular Oncology
  • European Institute of Oncology
  • CRO (Centro di Riferimento Oncologico) Aviano National Cancer Institute
  • Istituto Nazionale dei Tumori
  • Sapienza University of Rome
  • Linköping University
  • University of Florence
  • University of Cambridge
  • University of Southern California
  • QIMR Berghofer Medical Research Institute
  • Oregon Health & Science University
  • Dana-Farber Cancer Institute
  • University of São Paulo
  • Copenhagen University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • Adolescent, Adult, Alleles, BRCA1 Protein, BRCA2 Protein, Female, Genes, Reporter, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heterozygote, Humans, Mutation, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Young Adult, Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)164-71
Number of pages8
JournalNature Genetics
Volume47
Issue number2
Publication statusPublished - 2015 Feb
Publication categoryResearch
Peer-reviewedYes