Inactivation of MSH3 in Colorectal Cancer and Race

摘要 CRC在美国的发生表明，在公认的种族和 种族，其中非裔美国人表现出最高的发病率和死亡率。我们 观察到了DNA错配修复蛋白MSH3的一种新的“功能丧失”表型 通过促炎白介素6(IL6)将MSH3从细胞核(通常修复DNA的地方)穿梭出来 微卫星和双链断裂)到细胞质，在那里它不再能以重合的方式修复DNA 四核苷酸微卫星移码的堆积(称为EMAST，微卫星改变在 选定的四核苷酸重复)。这些与炎症相关的微卫星改变在 50%的散发性大肠癌与晚期疾病和较差的患者存活率有关。这 在非裔美国人中观察到炎症诱导的躯体MSH3缺陷的人数是白人的两倍 直肠癌，并与不良的患者预后有关。在这个提案中，我们假设MSH3 中断是非洲裔美国人结直肠癌晚期和生存不良的后果 病人。我们的初步数据表明，MSH3参与了同源的 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个 非裔美国人大肠癌中独特的体细胞有害MSH3突变尚未报道 公共数据库。我们已经鉴定了染色体9p24.2杂合性缺失(LOH)是 与EMAST相关，并极大地改变了初发CRC患者的生存率 EMAST和9p24.2杂合性缺失。在这项提案中，我们将研究MSH3功能障碍在其 对非裔美国人结直肠癌患者生存结局的贡献。我们的目标是评估MSH3的作用- 非裔美国人CRC中中断的双链断裂误修复，决定了6的功能 在非裔美国人癌中观察到独特的MSH3突变，并确定MSH3- 非裔美国人癌侵袭性染色体9p24.2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，这可能会导致穷人 与非裔美国结直肠癌患者相关的表型。

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.