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

Alexander GusevKate LawrensonXianzhi LinPaulo C LyraSiddhartha KarKevin C VavraFelipe SegatoMarcos A S FonsecaJanet M LeeTanya PejovicGang Liunull nullBeth Y KarlanMatthew L FreedmanHoutan NoushmehrAlvaro N A MonteiroPaul David Peter PharoahBogdan PasaniucSimon A Gayther
Published in: Nature genetics (2019)
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.
Keyphrases
  • genome wide
  • high grade
  • gene expression
  • dna methylation
  • genome wide association study
  • low grade
  • genome wide identification
  • high throughput
  • transcription factor