Inactivation of MSH3 in Colorectal Cancer and Race

MSH3 在结直肠癌和种族中的失活

• 批准号: 10808670
• 负责人: Hassan Ashktorab
• 金额: $ 43.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10808670
• 关键词: Inactivation; MSH3; Colorectal; Cancer; Race

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在美国的发生表明公认的种族和人群之间存在巨大差异 种族，其中非洲裔美国人的这种疾病的发病率和死亡率最高。 观察到诱导的 DNA 错配修复蛋白 MSH3 出现一种新的“功能丧失”表型 通过促炎性白细胞介素 6 (IL6) 将 MSH3 从细胞核（通常在细胞核中修复 DNA）中运送出来 微卫星和双链断裂）到细胞质，它不再能够以一致的方式修复 DNA 四核苷酸微卫星移码的积累（称为 EMAAST，微卫星变化升高） 选定的四核苷酸重复）。 占所有散发性 CRC 的 50%，与晚期疾病和患者生存率低有关。 炎症引起的体细胞 MSH3 缺陷在非裔美国人中的比例是白种人的两倍 直肠癌，并且与患者预后不良相关。在该提案中，我们考虑了 MSH3。 干扰导致非裔美国人结直肠癌晚期和生存率低下 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体我们已经确定了 6 种。 非裔美国人 CRC 中独特的体细胞有害 MSH3 突变尚未在 我们已经确定了染色体 9p24.2 杂合性丢失 (LOH) 的特征。 与 EMAAST 相关，并显着改变原发性 CRC 患者的生存率 EMAST 和 9p24.2 LOH 在本提案中，我们将研究 MSH3 功能障碍在其中的核心作用。 我们的目的是评估 MSH3- 对非裔美国 CRC 患者生存结果的贡献。 非裔美国人 CRC 中双链断裂误修复中断，确定 6 的功能 在非裔美国人 CRC 中观察到独特的 MSH3 突变，并确定 MSH3 的贡献 染色体 9p24.2 LOH 缺陷影响了非裔美国人 CRC 的攻击性。 该提案研究了可能导致贫困的缺陷 MSH3 蛋白的作用和贡献 与非裔美国 CRC 患者相关的表型。