Inactivation of MSH3 in Colorectal Cancer and Race

摘要 CRC在美国的发生率显示了公认种族之间的巨大差异， 种族，非洲裔美国人表现出这种疾病的发病率和死亡率最高。我们 已经观察到DNA错配修复蛋白MSH3的一种新的"功能丧失"表型， 通过促炎性白细胞介素-6（IL-6）将MSH3从细胞核（通常在细胞核中修复DNA）中穿梭出来， 微卫星和双链断裂）的细胞质，在那里它不再可以修复DNA与符合 四核苷酸微卫星移码的积累（称为EMAST， 选择的四核苷酸重复序列）。这些炎症相关的微卫星改变在 所有散发性CRC的50%，与晚期疾病和患者生存率低相关。这 在非裔美国人中观察到炎症诱导的体细胞MSH3缺陷是高加索人的两倍 直肠癌，并与患者预后不良相关。在这个提议中，我们假设MSH3 干扰导致非裔美国人CRC晚期和生存率低 患者我们的初步数据表明，明确的证据表明，MSH3参与了Homepage DNA双链断裂的修复以及防止非整倍体。我们发现6 非裔美国人CRC中独特的体细胞有害MSH3突变， 公共数据库。我们还发现了染色体9p24.2杂合性缺失（洛）， 与EMAST相关，并显著改变原发性CRC患者的生存率， EMAST和9p24.2洛缺失。在这个建议中，我们将研究MSH3功能障碍在其发病机制中的核心作用。 对非裔美国CRC患者的生存结局的贡献。我们的目标是评估MSH3的作用- 非裔美国人CRC中破坏的双链断裂错误修复，确定6 在非裔美国人CRC中观察到的独特MSH3突变，并确定MSH3- 在非裔美国人CRC的侵袭性中存在染色体9p24.2洛缺失。总体而言，这 一项提案研究了有缺陷的MSH3蛋白的作用和贡献，该蛋白可能导致穷人 与非裔美国人CRC患者相关的表型。

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.