Epigenetic dysregulation in APC-negative colorectal cancer

非裔美国人(AAs)的结直肠癌(CRC)发病率高于美国白人 总体来说，这种差异在发病年龄较早的人中更为严重。年龄的中位数 AAS的发病年龄为65岁，而NHW为72岁，早发型CRC的发生率是AAS的两倍 在卫生福利院。此外，流行病学证据表明，较年轻的鳞癌可能会有更快的 在致癌的各个步骤中取得进展。然而，年龄较小的结直肠癌并没有很好地表现出 我们无法解释AAS中发病率较高的原因。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，我们发现在肿瘤中缺乏突变的CRC过多 抑癌基因APC(APC突变阴性的CRCs)。微卫星稳定的APC突变阴性的大肠癌 与较年轻的诊断年龄、较少的体细胞突变以及微卫星和 染色体稳定性。重要的是，我们发现APC突变阴性的CRC表现出一种新的 甲基化特征是关键癌症驱动基因的甲基化水平增加，包括 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突变阴性癌的表观遗传异常导致特异的DNA甲基化改变和基因 维持干细胞样癌表型的调控网络。该项目的总体目标是 描述驱动这一新的CRC亚型的分子机制。我们有三个目标。目标1。 鉴定和描述AA-CRC中显著差异甲基化区域。假设：肿瘤-- 在APC突变阴性的癌组织中，特定的差异甲基化区域与癌变有关。 APC突变阴性的CRC将与较早的发病年龄和不同的分子和 临床病理特点。目的2.鉴定和鉴定差异表达的基因和 AA-CRC的监管网络。假设：维持干细胞样癌的特定调控网络 表型与APC突变阴性癌相关。目标3.确定驾驶员的基因依赖关系 在有机类癌模型中AA癌基因的表达。假设：抑制特定的WNT信号因子和 表观遗传调节剂将诱导APC突变阴性小鼠上皮细胞分化增加 与APC突变阳性有机物进行比较。拟议的研究将提供有关以下方面的基本知识 DNA甲基化和基因表达改变是AA细胞的潜在特征，并将成为癌细胞的特征 对化学挑战的反应。新知识将提供可翻译的信息，包括 诊断和预测生物标记物和精确医学方法，可用于治疗新的 AAS中出现过多的CRC亚型，与发病年龄较早有关。

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.