Elucidating the Role of MALAT1 Somatic Driver Mutations in Colorectal Cancer

肿瘤的发生和癌症的进展是由驱动基因的突变积累引起的。截然不同 在肿瘤进化过程中，驱动基因突变的组合相互作用，表现为 来自进化选择的突变共生。最近，长的非编码RNA(LncRNAs)已经被 被证明是癌症驱动基因。在这里，我们确定MALAT1是一种新的结直肠癌(CRC)驱动因素。 MALAT1 CRC突变在竞争的内源性(Cerna)-microRNA结合位点和CRC中丰富 携带MALAT1突变的人专门富含BRAF突变。这是第一次有系统地 确定了编码和lncRNA癌症驱动基因之间的合作实例。在这里，我们将测试 假设MALAT1竞争内源性RNA突变驱动结肠肿瘤的发生，并进行了验证 MALAT1突变促进结直肠癌生长和BRAF抑制剂耐药性的假说。我们的工作将提供 对MALAT1和MALAT1/BRAF突变的确切机制作用的前所未有的详细信息，并已 对推动临床精密医学测序小组研究MALAT1/BRAF突变的潜在影响 EGFR抑制剂治疗抵抗、锯齿状结直肠癌预后和BRAF/EGFR抑制剂联合治疗 临床试验。

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.