Inflammatory Differentiation of Colorectal Cancer Among African Americans

描述(申请人提供)：结直肠癌(CRC)是一种常见的疾病，但与其他种族群体相比，非洲裔美国人受到的不利影响不成比例，表现年龄较小，病情较晚期，死亡率较高。造成这种不利结果的原因尚不清楚。我们在初步数据中显示，来自基于人群的队列中的非裔美国人的CRC具有较低的微卫星不稳定性(MSI，由DNA错配修复[MMR]缺乏引起)，这是一种与更好的存活率相关的生物标记物，可能是由于周围的免疫细胞，但在选定的四核苷酸重复序列(EMAST)上有更高的微卫星改变的患病率，我们显示的一种生物标记物与腺瘤到癌的进展、晚期癌症和较高程度的肿瘤免疫细胞渗透有关。EMAST似乎是结直肠肿瘤的获得性缺陷，可能是肿瘤炎症的结果，并与“次要”MMR蛋白hMSH3表达的异质性丢失有关。我们假设MSI肿瘤的免疫细胞谱不同于EMAST肿瘤(分别在非裔美国人中发病率低和高)。在这项提案中，我们将探索结直肠癌免疫谱中的种族差异，包括生存预测，使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、结肠癌家族登记以及其他标本的样本和数据。我们将检查EMAST和MSI肿瘤的免疫图谱，以帮助确定与每个生物标记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之间的免疫图谱，以进一步关联差异。从这项研究中获得的信息可能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“轻微”和“重大”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.