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

7.项目摘要/摘要 遗传性癌症综合征是由癌症易感基因的胚系突变引起的，说明了 基因组信息，以量身定制医疗护理。林奇综合征是最常见的遗传性胃肠道癌症综合征 影响到美国120万人。它的流行情况类似于更广为人知的遗传性乳房和卵子- 伊恩癌症综合症。林奇综合征是由四个错配修复基因中的一个突变引起的。终生结直肠可以- 林奇综合征的CER风险取决于致病基因，并且是高度可变的，范围在10%-80%之间，相差8倍- 安斯。目前，Lynch综合征的结直肠癌治疗策略是统一的，包括终生每年 到每两年一次的侵入性筛查测试和预防性风险降低手术。然而，考虑到基因依赖的可变性 癌症风险，与著名的密集临床管理相关的患者负担，以及过度/未充分利用的可能性- 因此，迫切需要循证确定基因依赖型结直肠癌的临床治疗。 Lynch 综合征。这个国家癌症研究所(NCI)K07职业发展奖的总体目标是确定- 在Lynch综合征中依赖MAL基因的结直肠癌的预防和治疗策略，应用决策分析，方法 气味是卫生服务研究的支柱。目标1和目标2产生关键输入、基因依赖的结直肠癌风险和 分别利用推荐护理来开发目标3中的马尔可夫模型，该模型将确定最优 结直肠癌在Lynch综合征中的基因治疗。这项研究的结果将有助于确保适当的使用 为林奇综合征患者提供更多的临床护理，使该领域更接近精密医学的承诺，并实现 NCI的任务是“将基因组带到诊所”。沙拉夫博士是一名胃肠病专家，也是一名初出茅庐的卫生服务研究员。 专注于癌症遗传学的临床研究。他的职业目标是成为一名独立资助的内科医生-科学家，拥有 癌症相关决策分析中的TISE。建议的K07奖将使他在进行荟萃分析和 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本方法 模型的校准和验证。他还将学习马尔可夫模型本身的操作。总而言之，这项医疗服务技能- SET用途广泛，可用于多种疾病。他的长期目标是领导一个专注于癌症的循证PRAC- Tice Center。NCI K07奖将为验证马尔可夫模型开发的R01应用程序提供初步数据。 在AIM 3中开放并扩展它，以探索特定性别的结直肠癌风险和子宫内膜的基因特定管理 和卵巢癌(也是与林奇有关的)，最终为与NCI的癌症干预进行比较建模奠定了基础- 为基因依赖型临床提供国家卫生政策建议的监测和监测建模网络 林奇综合征的管理。

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.