Inflammatory Differentiation of Colorectal Cancer Among African Americans

描述（由申请人提供）：结直肠癌（CRC）是一种常见疾病，但与其他种族群体相比，对非裔美国人的影响不成比例，表现为年龄较小，阶段较晚，死亡率较高。这种不良结果的原因尚不清楚。我们的初步数据显示，来自人群队列的非裔美国人的CRC的微卫星不稳定性患病率较低（MSI，由"主要" DNA错配修复[MMR]缺陷引起），这是一种与更好的生存相关的生物标志物，推测是由于周围的免疫细胞，但在选定的四核苷酸重复序列（EMAST）处具有更高的微卫星改变发生率，我们发现的一种生物标志物与腺瘤到癌的进展、晚期癌症和更高程度的肿瘤免疫细胞浸润相关。EMAST似乎是结直肠肿瘤中的获得性缺陷，其可能是肿瘤炎症的结果，并且与"次要" MMR蛋白hMSH3的表达的异质性损失相关。我们假设MSI肿瘤的免疫细胞谱与EMAST肿瘤不同（在非裔美国人中分别为低和高患病率）。在本提案中，我们将利用来自北卡罗来纳州结肠癌研究、北卡罗来纳州直肠癌研究、结肠癌家族登记处以及其他标本的样本和数据，探讨结肠直肠癌免疫特征的种族差异，包括生存率统计。我们将检查EMAST和MSI肿瘤的免疫特征，以帮助确定与每种生物标志物相关的免疫细胞类型。我们还将比较种族和基因组不稳定性之间的免疫谱，以进一步关联差异。从这项提案中获得的信息可以解释在结直肠癌中观察到的一些种族差异，并指导未来对获得性"次要"和"主要" MMR缺陷在激活免疫系统方面的差异的研究。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a common disease but disproportionately adversely affects African Americans over other racial groups, with younger age of presentation, a more advanced stage, and higher mortality. The reason for this adverse outcome is not clear. We show in preliminary data that CRCs from African Americans from a population-based cohort have a lower prevalence of microsatellite instability (MSI, caused by "major" DNA mismatch repair [MMR] deficiency), a biomarker associated with better survival presumably due to surrounding immune cells, but have a higher prevalence of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a biomarker we show associated with adenoma-to-carcinoma progression, advanced staged cancers, and higher degrees of tumor immune cell infiltration. EMAST appears to be an acquired defect in colorectal tumors that may be a result of tumor inflammation, and is associated with heterogeneous loss of expression of the "minor" MMR protein hMSH3. We hypothesize that the immune cell profiles from MSI tumors are different than EMAST tumors (low and high prevalence among African Americans, respectively). In this proposal, we will explore racial differences in immune profiles within colorectal cancers, including survival prognostication, utilizing samples and data from the North Carolina Colon Cancer Study, the North Carolina Rectal Cancer Study, the Colon Cancer Family Registry, as well as other specimens. We will examine the immune profiles of EMAST and MSI tumors to help determine the type of immune cells associated with each biomarker. We will also compare immune profiles between race and genomic instability to further correlate differences. The information obtained from work in this proposal may explain some of the racial differences observed in colorectal cancer, and direct future investigation on differences between acquired "minor" and "major" MMR defects on activating the immune system.