Inflammatory Differentiation of Colorectal Cancer Among African Americans

非裔美国人结直肠癌的炎症分化

• 批准号: 8538900
• 负责人: John M Carethers
• 金额: $ 27.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538900
• 关键词: Affect; African American; Age; Behavior; Biological Markers; Carcinoma; Caucasians; Caucasoid Race; Cells; Colon Carcinoma; Colorectal Cancer; Colorectal Neoplasms; DNA; Data; Defect; Diagnostic Neoplasm Staging; Disease; Freezing; Future; Genetic; Genomic Instability; High Prevalence; Immune; Immune response; Immune system; Immunotherapy; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Investigation; Location; Low Prevalence; Michigan; Microsatellite Instability; Microsatellite Repeats; Minor; Mismatch Repair; Molecular Profiling; North Carolina; Patients; Prevalence; Proteins; Race; Rectal Cancer; Registries; Resources; Sampling; Specimen; Staging; Testing; Tetranucleotide Repeat; Tumor Bank; Universities; Work; adenoma; adverse outcome; cohort; colon cancer family registry; improved; mortality; novel strategies; patient population; population based; racial difference; tumor

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.

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，结直肠癌对非裔美国人的不利影响更大，发病年龄更小，分期更晚，死亡率更高。造成这种不良结果的原因尚不清楚。我们在初步数据中显示，来自基于人群的非裔美国人的 CRC 的微卫星不稳定性（MSI，由“主要”DNA 错配修复 [MMR] 缺陷引起）的发生率较低，这是一种与更好的生存相关的生物标志物，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 (EMAAST) 处的微卫星改变升高的发生率较高， 我们展示了与腺瘤到癌的进展、晚期癌症和更高程度的肿瘤免疫细胞浸润相关的生物标志物。 EMAST 似乎是结直肠肿瘤中的一种获得性缺陷，可能是肿瘤炎症的结果，并且与“次要”MMR 蛋白 hMSH3 表达的异质性丧失相关。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患病率和高患病率）。在本提案中，我们将利用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，探讨结直肠癌免疫特征的种族差异，包括生存预测。我们将检查 EMAAST 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特征，以进一步关联差异。从本提案中的工作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“轻微”和“主要”MMR缺陷在激活免疫系统方面的差异进行研究。