Epigenetic dysregulation in APC-negative colorectal cancer

APC 阴性结直肠癌的表观遗传失调

• 批准号: 10223247
• 负责人: Nathan A. Ellis
• 金额: $ 49.99万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10223247
• 关键词: APC gene; APC mutation; African American; Age; Age of Onset; Algorithms; Automobile Driving; Cancer Model; Cell Maintenance; Cells; Chemicals; Chicago; Chromosomal Stability; Clinical; Colorectal Cancer; DNA Methylation; Data; Dependence; Development; Diagnosis; Epidemiology; Epigenetic Process; Epithelial; Exhibits; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Goals; Incidence; Knowledge; Latino; Malignant Neoplasms; Methylation; Microsatellite Repeats; Modeling; Molecular; Mutation; Not Hispanic or Latino; Organoids; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Population; Public Health; Race; Regulator Genes; Series; Somatic Mutation; Subgroup; System; Testing; Tumor Suppressor Genes; WNT Signaling Pathway; base; cancer cell; cancer diagnosis; cancer health disparity; cancer stem cell; cancer subtypes; carcinogenesis; cellular imaging; chromosome mutation; diagnostic biomarker; differential expression; drug sensitivity; early onset colorectal cancer; high dimensionality; innovation; molecular subtypes; mortality; mutational status; novel; precision medicine; predictive marker; prevent; response; small molecule libraries; stem; stem cells; transcriptomics; tumor

The incidence of colorectal cancer (CRC) is higher in African Americans (AAs) compared with US whites (NHWs) overall, but the disparity is more extreme in persons with earlier age of onset. The median age of onset is 65 in AAs compared to 72 in NHWs, and early-onset CRC is more than twice as frequent in AAs than in NHWs. In addition, epidemiologic evidence suggests that younger age CRCs may have a more rapid progression through the steps of carcinogenesis. Yet, younger age CRC is not well characterized in any population, and we have no explanation for its higher incidence in AAs. In a recent genomic analysis of a series of Chicago African American CRC cases, we found an excess of CRCs lacking mutation in the tumor suppressor gene APC (APC mutation-negative CRCs). Microsatellite stable APC mutation-negative CRCs were associated with younger age of diagnosis, fewer numbers of somatic mutations, and microsatellite and chromosome stability. Importantly, we discovered that APC mutation-negative CRCs exhibited a novel methylation profile characterized by increased levels of methylation in key cancer driver genes including those in stem-cell maintenance and the WNT signaling pathway. Based on our preliminary data, we hypothesize that epigenetic dysregulation in APC mutation-negative CRCs drives specific DNA methylation changes and gene regulatory networks that maintain a stem-like cancer phenotype. The overall goal of the project is to characterize the molecular mechanisms that drive this novel subtype of CRCs. We have three aims. Aim 1. Identify and characterize significant differentially methylated regions in AA CRC. Hypothesis: Tumor- specific differentially methylated regions are associated with carcinogenesis in APC mutation-negative CRCs. APC mutation-negative CRCs will be associated with earlier age of onset and with distinct molecular and clinicopathological features. Aim 2. Identify and characterize differentially expressed genes and regulatory networks in AA CRCs. Hypothesis: Specific regulatory networks that maintain a stem-like cancer phenotype are associated with APC mutation-negative CRCs. Aim 3. Determine driver gene dependencies of AA CRCs in organoid cancer models. Hypothesis: Suppression of specific WNT signaling factors and epigenetic modulators will induce increased epithelial differentiation in APC mutation-negative organoids in comparison to APC mutation-positive organoids. The proposed studies will provide essential knowledge of the DNA methylation and gene expression changes underlying AA CRCs and will characterize cancer cell responses to chemical challenge. The new knowledge will provide translatable information, including diagnostic and predictive biomarkers and precision-medicine approaches, that could be used to treat a novel subtype of CRC that occurs in excess in AAs and is associated with earlier age of onset.

与美国白人相比，非裔美国人 (AA) 结直肠癌 (CRC) 的发病率更高 (NHW) 总体而言，但在发病年龄较早的人群中，这种差异更为极端。中位年龄为 AA 中的发病率为 65 例，而 NHW 中为 72 例，早发 CRC 的发生率在 AA 中是 NHW 的两倍多 在 NHW 中。此外，流行病学证据表明，年轻的结直肠癌可能有更快的发病速度。 通过癌发生的步骤进行进展。然而，年轻结直肠癌在任何疾病中都没有得到很好的表征。 人口，我们无法解释其在 AA 中的较高发病率。在最近的一项基因组分析中 在一系列芝加哥非裔美国人结直肠癌病例中，我们发现了过量的肿瘤缺乏突变的结直肠癌 抑制基因 APC（APC 突变阴性 CRC）。微卫星稳定 APC 突变阴性 CRC 与诊断年龄较小、体细胞突变数量较少以及微卫星和 染色体稳定性。重要的是，我们发现 APC 突变阴性 CRC 表现出一种新的 甲基化谱的特点是关键癌症驱动基因的甲基化水平增加，包括 干细胞维持和 WNT 信号通路。根据我们的初步数据，我们假设 APC 突变阴性 CRC 中的表观遗传失调驱动特定的 DNA 甲基化变化和基因 维持干细胞样癌症表型的调控网络。该项目的总体目标是 描述驱动这种新型 CRC 亚型的分子机制。我们有三个目标。目标1。 识别并表征 AA CRC 中显着差异的甲基化区域。假设：肿瘤- 特定差异甲基化区域与 APC 突变阴性 CRC 的癌变相关。 APC 突变阴性 CRC 与发病年龄较早以及不同的分子和特征有关。 临床病理特征。目标 2. 识别和表征差异表达基因 AA CRC 中的监管网络。假设：维持干细胞样癌症的特定调控网络 表型与 APC 突变阴性 CRC 相关。目标 3. 确定驱动基因依赖性 类器官癌症模型中的 AA CRC。假设：特定 WNT 信号因子的抑制和 表观遗传调节剂将诱导 APC 突变阴性类器官的上皮分化增加 与 APC 突变阳性类器官的比较。拟议的研究将提供以下方面的基本知识： DNA 甲基化和基因表达改变 AA CRC 的基础，并将表征癌细胞 对化学挑战的反应。新知识将提供可翻译的信息，包括 诊断和预测生物标志物以及精准医疗方法，可用于治疗新的疾病 CRC 亚型，在 AA 中发生过多，且与发病年龄较早有关。