Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Research output: Contribution to journalJournal articleResearchpeer-review

  • Kate Lawrenson
  • Qiyuan Li
  • Siddhartha Kar
  • Ji-Heui Seo
  • Jonathan Tyrer
  • Tassja J Spindler
  • Janet Lee
  • Yibu Chen
  • Alison Karst
  • Ronny Drapkin
  • Katja K H Aben
  • Hoda Anton-Culver
  • Natalia Antonenkova
  • Helen Baker
  • Elisa V Bandera
  • Yukie Bean
  • Matthias W Beckmann
  • Andrew Berchuck
  • Maria Bisogna
  • Line Bjorge
  • Natalia Bogdanova
  • Louise A Brinton
  • Angela Brooks-Wilson
  • Fiona Bruinsma
  • Ralf Butzow
  • Ian G Campbell
  • Karen Carty
  • Jenny Chang-Claude
  • Georgia Chenevix-Trench
  • Anne Chen
  • Zhihua Chen
  • Linda S Cook
  • Daniel W Cramer
  • Julie M Cunningham
  • Cezary Cybulski
  • Agnieszka Dansonka-Mieszkowska
  • Joe Dennis
  • Ed Dicks
  • Jennifer A Doherty
  • Thilo Dörk
  • Andreas du Bois
  • Matthias Dürst
  • Diana Eccles
  • Douglas T Easton
  • Robert P Edwards
  • Ursula Eilber
  • Høgdall, Estrid Vilma Solyom
  • Høgdall, Claus Kim
  • Allan Jensen
  • Kjær, Susanne Krüger
  • Australian Ovarian Cancer Study Group
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Original languageEnglish
Article number8234
JournalNature Communications
Volume6
Number of pages14
ISSN2041-1723
DOIs
Publication statusPublished - Sep 2015

    Research areas

  • Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Neoplasm Proteins, Neoplasms, Glandular and Epithelial, Nuchal Cord, Ovarian Neoplasms, Protein Binding, Quantitative Trait Loci

ID: 162454509