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

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. alexander_gusev@dfci.harvard.edu.
2
Division of Genetics, Brigham & Women's Hospital, Boston, MA, USA. alexander_gusev@dfci.harvard.edu.
3
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
4
Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
5
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
6
CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
7
Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
8
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA.
9
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
11
Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
12
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
13
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
14
Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

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.

PMID:
31043753
DOI:
10.1038/s41588-019-0395-x

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