Nature genetics, 2019-05, Vol.51 (5), p.815-823
2019
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- Autor(en) / Beteiligte
- Titel
- A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants
- Ist Teil von
- Nature genetics, 2019-05, Vol.51 (5), p.815-823
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. A multi-tissue transcriptome-wide association study based on genetic predictors of expression level and alternative splicing in relevant tissues identifies 25 candidate genes associated with high-grade serous ovarian cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036eISSN: 1546-1718DOI: 10.1038/s41588-019-0395-xTitel-ID: cdi_proquest_miscellaneous_2218998146
- Format
- –
- Schlagworte
- 38, 45/43, 45/91, 631/208, 631/208/199, 631/208/205/2138, 631/67, 631/67/1517/1709, Agriculture, Alternative Splicing, Animal Genetics and Genomics, Biochemistry, Biomedical and Life Sciences, Biomedicine, Cancer genetics, Cancer Research, Carcinoma, Ovarian Epithelial - genetics, Cell Cycle Proteins - genetics, Cell Line, Tumor, Databases, Genetic, Disease susceptibility, Endosomal Sorting Complexes Required for Transport - genetics, Female, Gene expression, Gene Expression Regulation, Neoplastic, Gene Function, Gene Knockout Techniques, Gene loci, Genes, Genetic aspects, Genetic engineering, Genetic Predisposition to Disease, Genetic research, Genetic susceptibility, Genome-wide association studies, Genome-Wide Association Study, Genomes, Genomics, Genotype & phenotype, Health risk assessment, Human Genetics, Humans, Identification and classification, Models, Genetic, Myc protein, Nuclear Proteins - genetics, Oncogenes, Ovarian cancer, Ovarian Neoplasms - genetics, Polymorphism, Single Nucleotide, Prostate cancer, Quantitative genetics, Risk factors, Screens, Studies, Transcriptome, Tumorigenesis