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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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.
OriginalsprogEngelsk
Artikelnummer8234
TidsskriftNature Communications
Vol/bind6
Antal sider14
ISSN2041-1723
DOI
StatusUdgivet - sep. 2015

ID: 162454509