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

Ovarian Cancer Association Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)815-823
Number of pages9
JournalNature genetics
Volume51
Issue number5
DOIs
StatePublished - May 1 2019

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Transcriptome
Ovarian Neoplasms
Genes
Genome-Wide Association Study
Exons
Alleles
Ovarian epithelial cancer
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Genetics

Cite this

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

In: Nature genetics, Vol. 51, No. 5, 01.05.2019, p. 815-823.

Research output: Contribution to journalArticle

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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.",
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