Uncovering the Role of Colorectal Stem Cells on Disease Penetrance in Lynch Syndrome

项目摘要 Lynch综合征是一种常染色体显性遗传性疾病，易使患者主要发展为科洛- 直肠癌的估计终身风险高达80%，这是继发于生殖细胞的改变， DNA错配修复基因。然而，它有一个不完全的疾病发病率， 患者的基因型年龄和性别。外显率研究也关注流行病学因素 由于外源性物质代谢中的单基因-基因相互作用未能精确估计风险， 林奇综合征，从而导致锅炉板大肠癌筛查的建议。暴露于 非甾体类抗炎药，特别是阿司匹林，是唯一能够改变 疾病风险降低（60%）。我们的长期目标是解释在结直肠癌中观察到的差异， 通过了解大肠癌发生的分子机制， 林奇综合征，所以我们可以实施精确的筛查和化学预防。本申请的目的是-- 阳离子是表征细胞和分子的变化所诱导的化学预防与非甾体抗 炎症因子和他汀类药物对结直肠干细胞的作用，导致结直肠癌转移率降低。 我们的中心假设是，林奇综合征患者中结直肠癌发病率的变化是次要的， 直接涉及正常高危粘膜的结直肠干细胞龛的分子变化。的 支持这一建议的基本原理是基于我们的观察，即（1）Lynch的高危粘膜和息肉 与正常粘膜相比，综合征患者显示肠干细胞标记的转录差异 （2）辛伐他汀的化学预防诱导结直肠癌的深刻调节 在林奇综合征的肾脏特异性小鼠模型中的药物依赖性;（3）辛伐他汀的化学预防， 纳曲林降低肠干细胞标志物，同时增加高危患者的分化标志物 Lynch综合征动物模型的粘膜。我们建议达到以下三个具体目标：（1）界定 体内错配修复缺陷肠干细胞的特征;（2）评估 辛伐他汀和萘普生对错配修复缺陷的结直肠干细胞的化学预防干预 使用患者来源的类器官和3）评估干细胞和上皮分化标志物的变化， 在I期化学预防试验中，暴露于纳曲林的LS患者的正常结肠直肠粘膜活检。的 本研究的创新之处在于使用化学预防剂作为癌症转移的修饰工具， 探讨大肠干细胞及其相关分子通路在大肠癌变异中的作用 Lynch综合征的症状这一贡献将是重大的，因为它将导致发现钼- 癌症风险预测的学术标志物，将允许设计个性化的筛查和预防计划， Lynch综合征患者的治疗。

PROJECT SUMMARY Lynch syndrome is an autosomal dominant hereditary condition predisposing patients to develop mainly colo- rectal cancer with an estimated life-time risk as high as 80%, which is secondary to germline alterations in the DNA mismatch repair genes. However, it has an incomplete disease penetrance that varies widely depending on the genotype, age and gender of the patients. Penetrance studies looking into epidemiological factors as well as single gene-to-gene interactions within the metabolism of xenobiotics have failed to refine risk estimations in Lynch Syndrome, thus leading to boiler plate recommendations for colorectal cancer screening. Exposure to non-steroidal anti-inflammatory agents, in particular Aspirin, has been the only factor that has been able to modify disease penetrance (60% risk reduction). Our long-term goal is to explain the differences observed in colorectal penetrance in this patient population by understanding the molecular events driving colorectal carcinogenesis in Lynch Syndrome, so we can implement precision screening and chemoprevention. The objective of this appli- cation is to characterize the cellular and molecular changes induced by chemoprevention with non-steroidal anti- inflammatory agents and Statins on colorectal stem cells that lead to reduction of colorectal cancer penetrance. Our central hypothesis is that variation of colorectal cancer penetrance among Lynch Syndrome patients is sec- ondary to molecular changes directly involving the colorectal stem cell niche of the normal at-risk mucosa. The rationale supporting this proposal is based on our observations that (1) at-risk mucosa and polyps from Lynch Syndrome patients show transcriptional differences in intestinal stem cell signatures compared to normal mucosa of healthy controls; (2) chemoprevention with Simvastatin induces a profound modulation of colorectal cancer penetrance in an intestinal-specific mouse model of Lynch Syndrome; (3) chemoprevention with Simvastatin and Naproxen decreases intestinal stem cell markers and simultaneously increases differentiation markers in at-risk mucosa of Lynch Syndrome animal models. We propose to pursue the following three specific aims: (1) to define a signature of mismatch repair-deficient intestinal stem cells in vivo; (2) to assess the modulatory effect of Simvastatin and Naproxen as chemopreventive interventions on mismatch repair-deficient colorectal stem cells using patient-derived organoids and 3) to assess changes in stem cell and epithelial differentiation markers in normal colorectal mucosa biopsies of LS patients exposed to Naproxen in a Phase I chemoprevention trial. The innovation of this study lies in the use of chemopreventive agents as modifying tools of cancer penetrance to assess the role of colorectal stem cells and their related molecular pathways in the variation of colorectal cancer penetrance in Lynch Syndrome. This contribution will be significant because it will lead to the discovery of mo- lecular markers for cancer risk prediction that will allow designing personalized plans for screening and preven- tive interventions in Lynch Syndrome patients.