Transcriptome-wide association study to identify susceptibility genes for colorectal cancer

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SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-036 with a goal to support mentored cancer research career development for Dr. Chi Thi Du Tran, an early- stage low- and middle-income country (LMIC) investigator (ESLI) from Vietnam. Supported by a supplement to our on-going transcriptome-wide association study (TWAS) in colorectal cancer (CRC) (R37CA227130, PI: Dr. Guo) and guided by a mentoring team at the Vanderbilt University Medical Center (VUMC), Dr. Tran will lead a TWAS in Vietnam to build new research expertise on genetic epidemiology and bioinformatics, accelerate her career goal to become an independent researcher and leader in the research field of molecular epidemiology of cancer. The overarching goal of the proposed research is to translate genetic findings into disease prevention and treatment, and to accelerate CRC prevention program in Vietnam. CRC arises mostly through the progression of colorectal adenomas to carcinoma sequence. It is well recognized that dysregulated gene expression plays a critical role in driving the progression of adenoma to carcinoma. We hypothesis that genetic effects of some CRC susceptibility genes may primarily manifest during the adenoma to carcinoma transition and thus can easier or only be detected in studies directly involving adenomas tissues. Thus, investigation of genetic effects on gene expression in premalignant tissues along the developmental stages of CRC, as proposed in this supplement application, would not only provide a great training and career development to a high promising ESLI, but also strengthen the scientific rigor and expand research scope of the parent study. In this application, we propose to collaborate with Dr. Tran to build genetically predicted gene expression models using non-advanced and advanced colorectal adenoma tissues collected in a largest population-based study of CRC in Vietnam, the Vietnam Colorectal Cancer and Polyps Research (VinCAP; Dr. Tran, site-PI of the study), to improve discovering novel susceptibility genes for the risk of CRC in East Asians. The specific aims of the proposed supplement are: Aim 1: to build genetically predicted gene expression models using the colorectal adenoma tissues. Aim 2: to conduct TWAS using new expression prediction models built in Aim 1 among 72,272 individuals of East Asian descent. Aim 3: to provide Dr. Tran methodological training in genetic epidemiology and bioinformatics. The research activities proposed in the supplement research project will be carried out by Dr. Tran and her team in Vietnam. Research protocols and analytic pipelines established in the parent study will be used in supplement research and extensive training will be provided to Dr. Tran. We are confident that this mentored research will prepare Dr. Tran become an independent investigator and leader in the field of molecular and genetic epidemiology of cancer.