Epigenetic dysregulation in APC-negative colorectal cancer

APC 阴性结直肠癌的表观遗传失调

• 批准号: 10611424
• 负责人: Nathan A. Ellis
• 金额: $ 47.25万
• 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/10611424
• 关键词: APC gene; APC mutation; African American; African American population; 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; Disparity; Epidemiology; Epigenetic Process; Epithelium; Exhibits; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Goals; Image; Incidence; Knowledge; Latino Population; 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; Series; Somatic Mutation; Subgroup; System; Testing; Tumor Suppressor Genes; WNT Signaling Pathway; cancer cell; cancer diagnosis; cancer health disparity; cancer stem cell; cancer subtypes; carcinogenesis; chromosome mutation; diagnostic biomarker; differential expression; drug sensitivity; early onset colorectal cancer; gene regulatory network; 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（AAs）的结直肠癌（CRC）发病率更高 （NHWs）总体而言，但在发病年龄较早的人中，这种差异更为极端。的年龄中位数 AAs中的发病率为65例，而NHW中为72例，AAs中早发性CRC的发生率是NHW的两倍多。 在NHWs。此外，流行病学证据表明，年轻的CRC可能有更快的 通过癌变的步骤进展。然而，年轻的CRC在任何一种疾病中都没有很好的特征。 我们无法解释其在AA中的较高发生率。在最近的一项对一种 在一系列芝加哥非裔美国人CRC病例中，我们发现肿瘤中存在过量的CRC缺乏突变 抑制基因APC（APC突变阴性CRCs）。微卫星稳定APC突变阴性CRC 与较年轻的诊断年龄，较少的体细胞突变，微卫星和 染色体稳定性。重要的是，我们发现APC突变阴性的CRC表现出新的 甲基化谱的特征是关键癌症驱动基因中甲基化水平的增加，包括那些 在干细胞维持和WNT信号通路中的作用。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异性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 表征驱动这种新型CRCs亚型的分子机制。我们有三个目标。目标1. 鉴定和表征AA CRC中显著差异甲基化区域。假设：肿瘤- 特异性差异甲基化区域与APC突变阴性CRC的致癌作用相关。 APC突变阴性的CRC将与较早的发病年龄和不同的分子水平相关， 临床病理特征目标2.识别和表征差异表达的基因， 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 AA CRC在类器官癌模型中的作用。假设：特异性WNT信号传导因子的抑制， 表观遗传调节剂将诱导APC突变阴性类器官中上皮分化的增加， 与APC突变阳性类器官的比较。拟议的研究将提供有关 DNA甲基化和基因表达变化是AA CRCs的基础，并将表征癌细胞 应对化学挑战。新知识将提供可翻译的信息，包括 诊断和预测生物标志物和精确医学方法，可用于治疗新的 在AA中过量发生并与较早发病年龄相关的CRC亚型。

项目成果

Genetic Gastric Cancer Risk Syndromes.

• DOI: 10.1007/s11938-020-00312-z
• 发表时间: 2020-12
• 期刊: Current treatment options in gastroenterology
• 作者: Lerner BA;Llor X
• 通讯作者: Llor X