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Elucidating the Role of MALAT1 Somatic Driver Mutations in Colorectal Cancer

阐明 MALAT1 体细胞驱动突变在结直肠癌中的作用

基本信息

批准号：
10532219
负责人：
Steven M Lipkin
金额：
$ 38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-04 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532219
关键词：
APC mutation Alternative Splicing Automobile Driving BRAF gene Binding Binding Sites Biological Models Breast Carcinoma Cancer Prognosis Chemoprevention Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Code Colon Colonoscopy Colorectal Cancer Combined Modality Therapy Computing Methodologies Data Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Evolution FRAP1 gene Frequencies Gene Mutation Genes Genetic Transcription Genome Goals Growth Human In Vitro International Knock-in Laboratories MALAT1 gene MAP Kinase Gene Malignant Neoplasms Messenger RNA MicroRNAs Molecular Mutation Neoplasm Metastasis Neoplasms Oncogenes Organoids Pathway interactions Patients Pharmaceutical Preparations Play Primary carcinoma of the liver cells Prognosis Proteins RNA Resistance Role Signal Transduction Somatic Mutation System Testing The Cancer Genome Atlas Therapeutic Therapy Clinical Trials Transcript Tumor Suppressor Proteins Untranslated RNA Work Xenograft procedure cancer genome colon tumorigenesis colorectal cancer progression colorectal cancer risk driver mutation experience experimental study genome-wide high risk homologous recombination in vivo inhibitor inhibitor therapy innovation insight mutant neoplastic novel precision medicine stem cells tumor tumor progression tumorigenesis whole genome working group

项目摘要

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.

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确定为新型结直肠癌（CRC）驱动因素。 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