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

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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Fig. 1: Study schema.
Fig. 2: Ovary-specific TWAS association for ARL17A.
Fig. 3: SpTWAS association at PRC1 implicates a new target gene independent of genetic effects on total expression.
Fig. 4: CHMP4C splicing is associated with the EOC risk allele.
Fig. 5: Functional analyses show evidence of essentiality for three TWAS/spTWAS genes.

Data availability

Code, documentation for all methods and all trained TWAS models for all genes and splice variants have been made available on the TWAS/FUSION website (http://gusevlab.org/projects/fusion/). Full TWAS association statistics have been made available in an interactive database available at http://www.twas-hub.org..

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Acknowledgements

This work was supported by multiple grants: an NIH/NCI R21 award (grant no. CA22007801); an NIH/NCI U19 award as part of the Genetic Mechanisms in Oncology (GAME-ON) consortium (grant no. CA148112); an NIH/NCI R01 award (grant no. CA211707); an NIH/NCI R01 award (grant no. CA207456); an NIH/NCI R01 award (grant no. CA204954); and an NIH/NCI R01 award (grant no. CA227237). S.A.G. is additionally supported by the Barth Family Chair in Cancer Genetics at Cedars-Sinai Medical Center. K.L. is supported in part by a K99/R00 Pathway to Independence Award from the NIH (grant no. R00CA184415) and institutional support from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center. H.N. and M.A.S.F. are supported by grant nos. 2015/07925-5 and 2017/08211-1 from São Paulo Research Foundation. H.N. is also supported by an institutional grant (Henry Ford Hospital, A30935). This work was supported in part by the Ovarian Cancer Research Fund Alliance Program Project Development Grant (grant no. 373356; Co-Evolution of Epithelial Ovarian Cancer and Tumor Stroma). Additional support for this work came from NIH/NCI grant nos. 1R01CA211707 and 1R01CA207456 and Ovarian Cancer Research Foundation award no. 258807. The results shown in this article are in part based on data generated by the TCGA Research Network (http://cancergenome.nih.gov/). Some of the normal tissue specimens were collected as part of the USC Jean Richardson Gynecologic Tissue and Fluid Repository, which is supported by a grant from the USC Department of Obstetrics & Gynecology and the NCT Cancer Center Shared Grant award no. P30 CA014089 (to the Norris Comprehensive Cancer Center). A.G. is supported by R01-CA227237 and the Claudia Adams Barr Award. B.P. is supported by R01-HG009120, R21-CA220078 and U01-CA194393.

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A.G., K.L., P.D.P.P., B.P. and S.A.G. designed and performed the experiments, analyzed the data and wrote the paper. X.L., P.C.L., S.K., K.C.V., F.S., M.A.S.F., J.M.L., T.P. and G.L. designed and performed the experiments. A.G., K.L., B.Y.K., M.L.F., H.N., A.N.M., P.D.P.P., B.P. and S.A.G. participated in designing the study and supervised the project.

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Correspondence to Alexander Gusev.

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Gusev, A., Lawrenson, K., Lin, X. et al. A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants. Nat Genet 51, 815–823 (2019). https://doi.org/10.1038/s41588-019-0395-x

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