Gene Dependent Cancer Risk and Optimal Cancer Prevention Strategies in Lynch Syndrome

林奇综合征的基因依赖性癌症风险和最佳癌症预防策略

• 批准号: 9899680
• 负责人: Ravi Sharaf
• 金额: $ 17.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-11 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899680
• 关键词: Affect; Award; Calibration; Cancer Intervention and Surveillance Modeling Network; Cancer-Predisposing Gene; Caring; Centers for Disease Control and Prevention (U.S.); Clinic; Clinical; Clinical Management; Colonoscopy; Colorectal Cancer; Data; Databases; Decision Analysis; Development; Disease; Endometrial Carcinoma; Ensure; Evidence based practice; Expert Opinion; Funding; Gastroenterologist; Gender; Genes; Genome; Genomics; Germ-Line Mutation; Goals; Health; Health Policy; Health Services; Health Services Research; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Neoplastic Syndromes; Hereditary Nonpolyposis Colorectal Neoplasms; Human; Individual; Inherited; Investigation; K-Series Research Career Programs; Lead; Learning; Literature; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of ovary; Medical; Meta-Analysis; Methodology; Mismatch Repair; Modeling; Mutate; Mutation; National Cancer Institute; National Comprehensive Cancer Network; National Health Policy; Operative Surgical Procedures; Outcome; PMS2 gene; Patients; Physicians; Precision Medicine Initiative; Prevalence; Prevention strategy; Probability; Publishing; Recommendation; Research Personnel; Risk; Risk Estimate; Risk Management; Scientist; Screening for cancer; Suggestion; Syndrome; Testing; United States; United States Agency for Healthcare Research and Quality; Validation; Variant; Work; age related; base; cancer genetics; cancer prevention; cancer risk; cancer therapy; career; career development; clinical care; cohort; colorectal cancer prevention; colorectal cancer risk; comparative; comparative effectiveness; evidence base; experience; gene repair; innovation; markov model; population based; precision medicine; programs; prophylactic; risk variant; screening; skills; success; treatment strategy

7. PROJECT SUMMARY/ABSTRACT Hereditary cancer syndromes are caused by a germline mutation in a cancer susceptibility gene and illustrate the potential of genomic information to tailor medical care. Lynch Syndrome is the most common hereditary gastrointestinal cancer syndrome affecting 1.2 million people in the United States. Its prevalence is similar to the more well-known Hereditary Breast and Ovar- ian Cancer Syndrome. Lynch Syndrome is caused by a mutation in one of four mismatch repair genes. Lifetime colorectal can- cer risk in Lynch Syndrome is dependent on causative gene and is highly variable, ranging between 10-80%, an 8-fold differ- ence. At present, colorectal cancer management strategies in Lynch Syndrome are uniform, consisting of a lifetime of annual to biennial invasive screening tests and prophylactic risk-reducing surgery. However, given the variability in gene-dependent cancer risk, the patient burden associated with noted intensive clinical management, and the potential for over/under-utiliza- tion, there is a critical need for evidence-based determination of gene-dependent colorectal cancer clinical management in Lynch Syndrome. The overall goal of this National Cancer Institute (NCI) K07 Career Development Award is to identify opti- mal gene-dependent colorectal cancer prevention and treatment strategies in Lynch Syndrome, using decision analysis, a meth- odologic pillar of health services research. Aims 1 and 2 generate pivotal inputs, gene-dependent colorectal cancer risk and utilization of recommended care, respectively, for the development of a Markov Model in Aim 3 that will determine optimal colorectal cancer clinical management in Lynch Syndrome by gene. Results from this study will help ensure the appropriate use of clinical care for those with Lynch Syndrome, moving the field closer to the promise of Precision Medicine and fulfilling the NCI's mandate to “take the genome to the clinic.” Dr. Sharaf is a gastroenterologist and budding health services researcher with a clinical focus on cancer genetics. His career goal is to become an independently-funded physician-scientist with exper- tise in cancer-related decision analysis. The proposed K07 Award will give him experience in the conduct of meta-analysis and large database analysis. These methodologies are fundamental for devising precise inputs for Markov models and for Markov model calibration and validation. He will also learn the conduct of Markov-modeling itself. In total, this health-services skill- set is versatile and can be applied to a variety of diseases. His long-term goal is to lead a cancer-focused Evidence-based Prac- tice Center. This NCI K07 Award will produce preliminary data for R01 applications that validate the Markov Model devel- oped in Aim 3 and expand it to explore gender-specific colorectal cancer risk and gene-specific management for endometrial and ovarian cancers (also Lynch-related), to ultimately set the stage for comparative modeling with the NCI's Cancer Interven- tion and Surveillance Modeling Network to enable national health policy recommendations for the gene-dependent clinical management of Lynch Syndrome.

7.项目总结/摘要 遗传性癌症综合征是由癌症易感基因中的生殖系突变引起的，并说明了遗传性癌症综合征的潜力。 基因组信息来定制医疗护理。Lynch综合征是最常见的遗传性胃肠癌综合征 影响了美国120万人它的流行程度与更知名的遗传性乳腺癌和卵巢癌相似。 伊恩癌症综合征。林奇综合征是由四种错配修复基因之一的突变引起的。终生结肠直肠癌- Lynch综合征的cer风险取决于致病基因，并且高度可变，范围在10- 80%之间，8倍差异， 恩塞。目前，Lynch综合征的结直肠癌管理策略是统一的，包括终身的年度治疗， 到两年一次的侵入性筛查测试和预防性降低风险的手术。然而，考虑到基因依赖的变异性， 癌症风险、与显著强化临床管理相关的患者负担以及过度/不足利用的可能性， 因此，迫切需要以证据为基础确定基因依赖性结直肠癌的临床管理， 林奇综合征这个国家癌症研究所（NCI）K 07职业发展奖的总体目标是确定最佳的职业发展机会。 在Lynch综合征中，使用决策分析，一种方法， 卫生服务研究的口腔学支柱。目的1和2产生关键输入，基因依赖性结直肠癌风险和 利用建议的护理，分别为目标3中的马尔可夫模型的发展，将确定最佳的 大肠癌临床处理中Lynch综合征的基因分型。这项研究的结果将有助于确保适当使用 为林奇综合征患者提供临床护理，使该领域更接近精准医学的承诺， NCI的使命是“将基因组带到临床”。Sharaf博士是一位胃肠病学家和新兴的卫生服务研究人员 临床上专注于癌症遗传学。他的职业目标是成为一名独立资助的物理学家，科学家， 癌症相关决策分析。拟议的K 07奖将使他在进行荟萃分析方面获得经验， 大型数据库分析这些方法是为马尔可夫模型和马尔可夫模型设计精确输入的基础。 模型校正和验证。他还将学习马尔可夫模型本身的行为。总的来说，这种健康服务技能- 它是通用的，可以应用于各种疾病。他的长期目标是领导一个以癌症为重点的循证实践， 战术中心。NCI K 07奖将为R 01应用提供初步数据，以验证马尔可夫模型的发展。 在目标3中进行了扩展，以探索性别特异性结直肠癌风险和子宫内膜癌的基因特异性管理。 和卵巢癌（也与林奇有关），最终为与NCI的癌症干预比较建模奠定基础。 国家卫生政策的建议，为基因依赖的临床 Lynch综合征的治疗