Elucidating the Role of MALAT1 Somatic Driver Mutations in Colorectal Cancer

肿瘤发生和癌症进展是由驱动基因中突变的积累引起的。不同 驱动基因突变的组合在肿瘤演变过程中合作，通过增加的频率揭示， 进化选择中的突变共存。最近，长链非编码RNA（lncRNA）已经被发现。 是癌症的驱动基因。在这里，我们将MALAT 1鉴定为一种新的结直肠癌（CRC）驱动因子。 MALAT 1 CRC突变在竞争性内源性（ceRNA）-microRNA结合位点和CRC中富集 携带MALAT 1突变的人特异性富集BRAF突变。这是第一个系统地 确定了编码和lncRNA癌症驱动基因之间合作的实例。在这里，我们将测试 假设MALAT 1竞争性内源性RNA突变驱动结肠肿瘤发生，并测试 MALAT 1突变促进CRC生长和BRAF抑制剂耐药性的假说。我们的工作将提供 前所未有的细节MALAT 1和MALAT 1/BRAF突变的精确机制作用， 潜在的影响，以推动临床精确医学测序小组研究MALAT 1/BRAF突变， EGFR抑制剂治疗耐药性、锯齿状CRC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.