权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10056203
负责人：
Steven M Lipkin
金额：
$ 38.77万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056203
关键词：
APC mutation Alternative Splicing Automobile Driving BRAF gene Binding Binding Sites Biological Models Breast 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 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/antagonist 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突变的积累引起的。清楚的驱动基因突变的组合在肿瘤进化过程中相互配合，这一点通过增加的频率来揭示来自进化选择的突变共现。最近，长非编码RNA（lncRNA）已被被证明是癌症驱动基因。在这里，我们将 MALAT1 确定为一种新型结直肠癌 (CRC) 驱动因素。 MALAT1 CRC 突变富含竞争性内源 (ceRNA)-microRNA 结合位点和 CRC 携带 MALAT1 突变的人特别富集 BRAF 突变。这是第一个系统的确定了编码和 lncRNA 癌症驱动基因之间合作的例子。在这里，我们将测试假设 MALAT1 竞争性内源性 RNA 突变驱动结肠肿瘤发生，并测试假设 MALAT1 突变促进 CRC 生长和 BRAF 抑制剂耐药性。我们的工作将提供对 MALAT1 和 MALAT1/BRAF 突变的精确机制作用进行了前所未有的详细研究，并且推动 MALAT1/BRAF 突变临床精准医学测序小组研究的潜在影响 EGFR 抑制剂治疗耐药、锯齿状 CRC 预后和 BRAF/EGFR 抑制剂联合治疗临床试验。