A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants

Nat Genet. 2019 May;51(5):815-823. doi: 10.1038/s41588-019-0395-x. Epub 2019 May 1.

Abstract

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10-9), CHMP4C at 8q21 (P = 2 × 10-11) and a PRC1 junction at 15q26 (P = 7 × 10-9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Carcinoma, Ovarian Epithelial / genetics*
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Databases, Genetic
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Models, Genetic
  • Nuclear Proteins / genetics
  • Ovarian Neoplasms / genetics*
  • Polymorphism, Single Nucleotide
  • Transcriptome

Substances

  • Cell Cycle Proteins
  • Endosomal Sorting Complexes Required for Transport
  • KANSL1 protein, human
  • Nuclear Proteins
  • PRC1 protein, human
  • Snf7-3 protein, human