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

  • Author(s): Gusev, Alexander
  • Lawrenson, Kate
  • Lin, Xianzhi
  • Lyra, Paulo C
  • Kar, Siddhartha
  • Vavra, Kevin C
  • Segato, Felipe
  • Fonseca, Marcos AS
  • Lee, Janet M
  • Pejovic, Tanya
  • Liu, Gang
  • Ovarian Cancer Association Consortium
  • Karlan, Beth Y
  • Freedman, Matthew L
  • Noushmehr, Houtan
  • Monteiro, Alvaro N
  • Pharoah, Paul DP
  • Pasaniuc, Bogdan
  • Gayther, Simon A
  • et al.

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.

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