Elucidating the Role of MALAT1 Somatic Driver Mutations in Colorectal Cancer

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Tumorigenesis and cancer progression are caused by the accumulation of mutations in driver genes. Distinct combinations of driver gene mutations cooperate during tumor evolution, revealed by increased frequency of mutation co-occurrence from evolutionary selection. Recently, long noncoding RNAs (lncRNAs) have been shown to be cancer driver genes. Here we identified MALAT1 as a novel colorectal cancer (CRC) driver. MALAT1 CRC mutations are enriched in competing endogenous (ceRNA)-microRNA binding sites, and CRCs carrying MALAT1 mutations are specifically enriched for BRAF mutations. This is the first systematically identified example of cooperation between coding and lncRNA cancer driver genes. Here, we will test the hypothesis that MALAT1 competing endogenous RNA mutations drive colon tumorigenesis, and also test hypotheses that MALAT1 mutations promote CRC growth and BRAF inhibitor resistance. Our work will provide unprecedented detail into the precise mechanistic roles of MALAT1 and MALAT1/BRAF mutations, and has potential impact to drive clinical precision medicine sequencing panel studies of MALAT1/BRAF mutations in EGFR inhibitor therapy resistance, serrated CRC prognosis, and BRAF/EGFR inhibitor combination therapy clinical trials.