Genome-wide significant risk associations for mucinous ovarian carcinoma

Nat Genet. 2015 Aug;47(8):888-97. doi: 10.1038/ng.3336. Epub 2015 Jun 15.

Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Mucinous / genetics*
  • Base Sequence
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Chromosomes, Human, Pair 2 / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Ovarian Neoplasms / genetics*
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors

Substances

  • HOXD9 protein, human
  • Homeodomain Proteins
  • Neoplasm Proteins
  • Green Fluorescent Proteins

Grant support