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

揭示结直肠干细胞对林奇综合征疾病外显率的作用

• 批准号: 9763349
• 负责人: Eduardo Vilar Sanchez
• 金额: $ 31.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763349
• 关键词: Aberrant crypt foci; Address; Affect; Age; Animal Model; Aspirin; Automobile Driving; Biopsy; Cancer Burden; Cancer-Predisposing Gene; Chemoprevention; Chemopreventive Agent; Chronic; Colonoscopy; Colorectal; Colorectal Cancer; DNA; Data; Development; Differentiation Antigens; Disease; Endometrial Carcinoma; Epidemiologic Factors; Epithelial; Event; Exposure to; Gender; General Population; Genes; Genotype; Goals; Hereditary Nonpolyposis Colorectal Neoplasms; Incidence; Individual; Inherited; Intervention; Intestines; Knowledge; LGR5 gene; Lead; Lesion; Life; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Microscopic; Mismatch Repair; Mission; Molecular; Mucous Membrane; Naproxen; Non-Steroidal Anti-Inflammatory Agents; Organoids; Outcome; PMS2 gene; Pathway interactions; Patients; Penetrance; Phase; Physiological; Polyps; Prevalence; Preventive; Preventive Intervention; Proteomics; Public Health; Recommendation; Reporting; Research; Risk; Risk Reduction; Role; Secondary to; Simvastatin; Small Intestines; Stem cells; Time; United States National Institutes of Health; Validation; Variant; Xenobiotic Metabolism; adenoma; base; cancer biomarkers; cancer risk; colon carcinogenesis; colorectal cancer risk; colorectal cancer screening; daughter cell; design; differential expression; gene interaction; gene repair; high risk population; in vivo; in vivo Model; innovation; insertion/deletion mutation; lifetime risk; malignant stomach neoplasm; mouse model; patient population; personalized screening; proteomic signature; repaired; screening; stem cell differentiation; stem cell niche; tool; transcriptomics; transmission process

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.

项目总结 林奇综合征是一种常染色体显性遗传性疾病，患者容易发展为主要是结肠炎。 直肠癌的估计终身风险高达80%，这是继发于 DNA错配修复基因。然而，它有一种不完全的疾病外显性，根据不同的情况有很大的不同。 患者的基因、年龄和性别。外显性研究也探讨了流行病学因素 由于外源生物代谢中的单个基因对基因的相互作用未能改进风险估计，因此 Lynch综合征，因此导致了结直肠癌筛查的样板建议。暴露于 非类固醇抗炎药，特别是阿司匹林，一直是唯一能够改变 疾病外显率(风险降低60%)。我们的长期目标是解释在结直肠中观察到的差异 通过了解导致结直肠癌发生的分子事件在该患者群体中的外显性 林奇综合症，这样我们就可以实施精确的筛查和化学预防。这项申请的目的是- 阳离子是表征非甾体类抗肿瘤药物化学预防引起的细胞和分子变化。 结直肠癌干细胞上的炎性物质和他汀类药物，可降低结直肠癌的外显性。 我们的中心假设是，在林奇综合征患者中，结直肠癌外显率的变化是秒。 其次是分子变化，直接涉及正常高危粘膜的结直肠干细胞巢。这个 支持这一建议的理由是基于我们的观察：(1)林奇的高危粘膜和息肉 与正常粘膜相比，综合征患者的肠道干细胞特征表现出转录差异 (2)辛伐他汀对结直肠癌的化学预防作用 肠道特异性林奇综合征小鼠模型的外显性；(3)辛伐他汀和 萘普生降低高危患者肠道干细胞标记物，同时增加分化标记物 Lynch综合征动物模型的粘膜。我们建议达致以下三个具体目标：(1)界定 错配修复缺陷的肠道干细胞在体内的特征；(2)评估 辛伐他汀和萘普生对错配修复缺陷大肠干细胞的化学预防作用 使用患者衍生的器官和3)评估干细胞和上皮分化标记物的变化 在一项I期化学预防试验中，暴露于萘普生的LS患者的正常大肠粘膜活检。这个 这项研究的创新之处在于使用化学预防药物作为癌症外显性的调节工具 结直肠干细胞及其相关分子通路在结直肠癌发生发展中的作用 林奇综合征的外显性。这一贡献将是重大的，因为它将导致钼的发现。 癌症风险预测的学术标记，将允许设计个性化的筛查和预防计划- 对林奇综合征患者的预防性干预。