Inactivation of MSH3 in Colorectal Cancer and Race

MSH3 在结直肠癌和种族中的失活

基本信息

批准号：
10674712
负责人：
Hassan Ashktorab
金额：
$ 56.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674712
关键词：
9p24 African American African American population Aneuploidy Biological Process Caucasians Cell Nucleus Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Colorectal Cancer Copy Number Polymorphism Cytosol DNA DNA Double Strand Break DNA Repair Data Defect Disease Disparity Double Strand Break Repair Ethnic Origin Ethnic Population Functional disorder Genes Impairment Incidence Inflammation Inflammatory Interleukin-6 Loss of Heterozygosity MLH1 gene MSH2 gene MSH3 gene MSH6 gene Malignant Neoplasms Microsatellite Repeats Mutation PMS2 gene Patient-Focused Outcomes Patients Phenotype Process Proteins Race Rectal Cancer Reporting Role Signal Transduction Testing Tetranucleotide Repeat United States colon cancer patients cytokine homologous recombination loss of function mismatch repair protein 1 mortality novel patient retention prevent public database racial population repaired survival outcome

项目摘要

Abstract The occurrence of CRC in the United States shows a large disparity among recognized races and ethnicities, with African Americans demonstrating the highest incidence and mortality from this disease. We have observed a novel “loss of function” phenotype for the DNA mismatch repair protein MSH3 that is induced by pro-inflammatory interleukin-6 (IL6) to shuttle MSH3 from the nucleus (where it normally repairs DNA microsatellites and double strand breaks) to the cytosol, where it no longer can repair DNA with coincident accumulation of tetranucleotide microsatellite frameshifts (termed EMAST, elevated microsatellite alterations at selected tetranucleotide repeats). These inflammation-associated microsatellite alterations are observed in 50% of all sporadic CRCs and is associated with advance-staged disease and poor patient survival. This inflammation-induced somatic MSH3 defect is observed in twice as many African American than Caucasian rectal cancers, and is associated with poor patient outcome. In this proposal, we hypothesize that MSH3 disruption contributes to the consequence of advanced stage and poor survival in African American CRC patients. Our preliminary data demonstrates clear evidence that MSH3 participates in Homologous Recombination repair of DNA double strand breaks as well as prevents aneuploidy. We have identified 6 unique somatic deleterious MSH3 mutations among African American CRCs that have not been reported in public databases. And we have characterized that chromosome 9p24.2 loss of heterozygosity (LOH) is associated with EMAST, and dramatically modifies survival of patients whose primary CRC demonstrates EMAST and 9p24.2 LOH. In this proposal, we will examine the central role of MSH3 dysfunction in its contribution to the survival outcome of African American CRC patients. Our aim is to assess the role of MSH3- disrupted double strand break mis-repair among African American CRCs, determine the functionality of 6 unique MSH3 mutations observed in African American CRCs, and ascertain the contribution of MSH3- deficiency with chromosome 9p24.2 LOH in the aggressiveness of African American CRCs. Overall, this proposal examines the role and contribution of defective MSH3 protein that likely contributes to the poor phenotype associated with African American CRC patients.

抽象的 CRC在美国的发生显示公认的种族之间存在很大差异种族，非裔美国人表现出这种疾病的最高事件和死亡率。我们已经观察到DNA不匹配修复蛋白MSH3的新型“功能丧失”表型通过促炎性白介素6（IL6）从核中穿梭MSH3（通常在其中维修DNA 微卫星和双链断裂）到细胞质，在那里它不再可以用一致的DNA修复DNA 四核苷酸微卫星的累积（称为弹性，升高的微卫星改变升高）选定的四核苷酸重复序列）。这些在所有零星CRC的50％与预期疾病和患者生存不良有关。这炎症引起的体细胞MSH3缺陷在非洲裔美国人的两倍上观察到是白种人的两倍直肠癌，与患者差不良有关。在此提案中，我们假设MSH3 破坏导致了非裔美国人CRC的高级阶段和生存不佳的结果患者。我们的初步数据证明了MSH3参与同源的明确证据 DNA双链断裂的重组修复以及防止非整倍性。我们已经确定了6 非裔美国人CRC中独特的躯体有害MSH3突变，尚未报道公共数据库。我们已经表征了9p24.2杂合性（LOH）的染色体损失是与弹药相关，并大大修改了主要CRC证明的患者的存活率 Emast和9p24.2 loh。在此提案中，我们将研究MSH3功能障碍在其中的核心作用对非裔美国人CRC患者的生存结果的贡献。我们的目的是评估MSH3-的作用非裔美国人CRC中破坏双链断裂的错误修复，确定功能6 在非裔美国人CRC中观察到的独特MSH3突变，并确定MSH3-的贡献非裔美国人CRC侵略性的9p24.2染色体的缺乏。总体而言，这提案检查可能有助于贫困的MSH3蛋白有缺陷的MSH3蛋白的作用和贡献与非裔美国人CRC患者相关的表型。