Abstract 30: Cross-cancer cross-tissue transcriptome-wide association study (TWAS) of 11 cancers identifies 56 novel genes
Authors: Feng Helian , Majumdar Arunabha , Pasaniuc Bogdan , Chen Hongjie , Lindström Sara ,   BCAC, OCAC, PRACTICAL, Huyghe Jeroen , Schmit Stephanie L. , O'Mara Tracy A. , Thompson Deborah J. , MacGregor Stuart , Brennan Paul , McKay James , Houlston Richard S. , Melin Beatrice S. , Amos Christopher , Cus Anne E. , Iles Mark M. , Kar Siddhartha , Pharoah Paul , Hung Rayjean J. , Kraft Peter 
Published: September 2020

Abstract
Although cancer is a heterogeneous disease, there are shared hallmark mechanisms across multiple tumor types. Because of this, identifying genes associated with multiple cancer types has the potential to shed light on general oncogenic mechanisms. Conversely, integrating evidence for genetic association across multiple cancers could identify novel genes missed in single-cancer analyses. Transcriptome Wide Association Studies (TWAS) have been successful in identifying genes associated with individual cancers. TWAS test whether genetically-predicted tissue-specific gene expression levels are associated with cancer risk. Although cross-cancer genome-wide association studies (GWAS) analyses have been performed previously, no cross-cancer TWAS has been conducted to date. Here, we implement a pipeline to perform cross-cancer, cross-tissue TWAS analysis. We use newly-developed multi-trait TWAS test statistics to integrate the TWAS results for association between 11 separated cancers and predicted gene expression in each of 43 GTEx tissues; these include a "sum" test and a "variance components" test, analogous to fixed- and random-effects meta-analyses. We then integrated the results across different tissues using the Aggregated Cauchy Association Test (ACAT), a novel powerful and robust test for combining association results under general correlation patterns. A total of 403 genes were significantly associated with at least one cancer type using predicted gene expression for at least one tissue (p&lt;0.05/899,338, Bonferroni adjusted for the total number of gene-cancer-tissue combinations tested); 96 additional genes were identified when combining test results across cancers (p&lt;0.05/81,758, adjusting for the total number of gene-tissue combinations tested); and 35 additional genes when further combining test results across tissue (p&lt;0.05/12,001, adjusting for the number of genes tested). Among these significant genes, 70 were not near previously-published GWAS index variants (&gt;250 kb distant). 14 of the 70 novel genes were identified from the single cancer single tissue test; an additional 43 were identified with the cross-cancer test; and another 13 were identified when further combining the results across tissues. The newly identified genes include RBBP8, which regulates cell proliferation and modulates BRCA1-mediated DNA repair, and TP53BP1, which is involved in double-strand break repair. Other newly identified genes are involved in chromatin structure, tumorigenesis, apoptosis, transcriptional regulation, DNA repair, immune system, oxidative damage and cell cycle, proliferation, progression, shape, structure, and migration.
Citation Format: Helian Feng, Arunabha Majumdar, Bogdan Pasaniuc, Hongjie Chen, Sara Lindström, BCAC, OCAC, PRACTICAL, Jeroen Huyghe, Stephanie L. Schmit, Tracy A. O'Mara, Deborah J. Thompson, Stuart MacGregor, Paul Brennan, James McKay, Richard S. Houlston, Beatrice S. Melin, Christopher Amos, Anne E. Cus, Mark M. Iles, Siddhartha Kar, Paul Pharoah, Rayjean J. Hung, Peter Kraft. Cross-cancer cross-tissue transcriptome-wide association study (TWAS) of 11 cancers identifies 56 novel genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 30.