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: 9377879
• 负责人: Eduardo Vilar Sanchez
• 金额: $ 33.07万
• 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/9377879
• 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; Epidemiological 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; TACSTD1 gene; Time; United States National Institutes of Health; Validation; Variant; Xenobiotic Metabolism; adenoma; base; cancer biomarkers; cancer risk; colon carcinogenesis; colorectal cancer screening; daughter cell; design; differential expression; gene interaction; gene repair; high risk population; in vivo; in vivo Model; innovation; insertion/deletion mutation; 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.

项目摘要 林奇综合征是一种常染色体显性的遗传病，使患者易于发展，主要发育 直肠癌估计的终身风险高达80％，这是继发于种系的变化 DNA不匹配修复基因。但是，它具有不完全的疾病渗透率，根据 关于患者的基因型，年龄和性别。外观研究还研究了流行病学因素 由于异种生物的代谢中的单个基因与基因相互作用未能完善风险估计 Lynch综合征，因此导致了锅炉板建议进行结直肠癌筛查。接触 非甾体类抗炎药，尤其是阿司匹林，一直是唯一能够修改的因素 疾病渗透率（降低风险60％）。我们的长期目标是解释大肠观察到的差异 通过了解驱动结直肠癌发生的分子事件，在该患者人群中的外观 林奇综合征，因此我们可以实施精确筛查和化学预防。该应用的目的 阳离子是为了表征由非甾体抗抗抗抗素的化学预防引起的细胞和分子变化 结直肠干细胞上的炎症剂和他汀类药物导致结直肠癌的渗透率降低。 我们的中心假设是，林奇综合征患者中结直肠癌的渗透率的变化是 直接涉及正常高危粘膜的结直肠干细胞壁ni的分子变化。这 支持该提案的理由是基于我们的观察结果，即（1）林奇高风险粘膜和息肉 综合征患者与正常粘膜相比显示肠道干细胞特征的转录差异 健康对照； （2）用辛伐他汀的化学预防诱导大肠癌的深刻调节 在lynch综合征的肠道特异性小鼠模型中的渗透； （3）用辛伐他汀和 萘普生减少肠道干细胞标记，同时增加危险中的分化标记 林奇综合征动物模型的粘膜。我们建议追求以下三个具体目标：（1）定义 在体内缺乏缺陷的肠道干细胞不匹配修复的标志； （2）评估 辛伐他汀和萘普生作为对不匹配修复缺陷的结直肠干细胞的化学预防干预措施 使用患者衍生的类器官和3）评估干细胞和上皮分化标记的变化 在I期化学预防试验中暴露于萘普生的LS患者的正常结直肠粘膜活检。这 这项研究的创新在于使用化学预防剂作为修改癌症外渗工具 评估结直肠干细胞及其相关分子途径在结直肠癌变异中的作用 林奇综合征的外观。这项贡献将是重要的，因为它将导致发现 癌症风险预测的障碍标记，将允许设计个性化计划以进行筛查和预见 林奇综合征患者的干预措施。