Ovarian Cancer and Mismatch Repair Deficiency

描述(申请人提供)：卵巢癌在美国女性癌症发病率和癌症死亡率中均排名第五，在妇科癌症中死亡率最高，大多数患者表现为晚期转移性疾病。传统上，大多数癌症都被当作一种疾病来治疗，而且治疗是基于分期和分级的。正在出现的数据显示，根据癌症的遗传病因，对治疗的反应可能会有所不同。更好地了解导致癌症演变和肿瘤异质性的分子事件应该会导致更具体的治疗方案。 在遗传性和散发性癌症的发病机制中，最明确的分子通路之一涉及错配修复(MMR)通路，该通路导致微卫星不稳定性(MSI)。MSI可能是由遗传(即：MMR基因的胚系突变，包括MLH1、MSH2和MSH6)和表观遗传(即：MLH1启动子超甲基化)机制引起的。本提案的目的是量化由于错配修复基因导致的卵巢肿瘤的比例，并描述这一组肿瘤的特征。我们能够根据卵巢癌的遗传基础对其进行分类，这为改进癌症预防和高危女性筛查、基于分子标志物的诊断和预后以及个性化治疗的发展提供了希望。 到目前为止，只有几项针对卵巢癌MMR的小型研究，没有一项是以人群为基础的。这在一定程度上是因为很难招募到大量具有人口代表性的卵巢癌患者。拟议的研究之所以可行，只是因为现有的三项北美人口研究的数据和样本已有大量可用资源，这三项研究是迄今为止北美大多数人口研究的基础。这项研究将包括莫菲特癌症中心、杜克综合癌症中心和多伦多大学的2200例上皮性卵巢癌，这将是世界上最大的上皮性卵巢癌收集。将对所有卵巢癌患者的石蜡包埋肿瘤样本进行分析，以进行MSI测试和调查MMR基因蛋白的表达。在那些具有MSI-H状态或MMR基因蛋白表达缺失的样本中，将进行表观遗传学(MLH1启动子超甲基化)和遗传学(种系MMR突变)的研究。 确定MSI-H卵巢肿瘤病因的因素的澄清与多达五分之一患有这种致命疾病的患者相关，因此这些数据可能有助于推进几个领域的临床实践，包括风险分层、行为调整，并最终具有治疗意义。

DESCRIPTION (provided by applicant): Ovarian cancer ranks fifth in both cancer incidence and cancer mortality in U.S. women and has the highest mortality rate among gynecologic cancers, with most patients presenting with late stage metastatic disease. Traditionally, most carcinomas have been treated as though they represent a single disease, and treatments have been based on stage and grade. Data is emerging that the response to treatments may differ, depending on the genetic etiology of the cancer. A better understanding of the molecular events that lead to the evolution of cancer and underlie tumor heterogeneity should lead to more specific treatment regimens. One of the best defined molecular pathways involved in both inherited and sporadic cancer pathogenesis involves the mismatch repair (MMR) pathway, which leads to microsatellite instability (MSI). MSI may result from both genetic (i.e.: germline mutations in the MMR genes, including MLH1, MSH2, and MSH6) and epigenetic (i.e.: MLH1 promoter hypermethylation) mechanisms. It is the purpose of the present proposal to quantify the proportion of ovarian tumors due to the mismatch repair genes and to characterize the tumors in this group. Our ability to classify ovarian cancers by their genetic basis offers promise for improvements in cancer prevention and screening of high risk women, in basing diagnosis and prognosis on molecular markers, and in development of individualized treatments. To date, only a few small studies of MMR in ovarian cancer have been performed and none have been population-based. This is in part due to the difficulty in recruiting large numbers of patients with ovarian cancer who are representative of the population. The proposed study is feasible to conduct only because of the extensive resources already available through the use of data and samples from three existing North American population-based studies, representing the majority of population-based cases in North America to date. This study will include 2200 incident epithelial ovarian cancers based at the Moffitt Cancer Center, Duke Comprehensive Cancer Center, and the University of Toronto and will be the largest collection of its type in the world. Paraffin-embedded tumor samples will be analyzed from all subjects with incident ovarian cancers to perform MSI testing and investigate MMR gene protein expression. In those samples with MSI-H status or with loss of expression of MMR gene proteins, epigenetic (MLH1 promoter hypermethylation) and genetic (germline MMR mutations) will be investigated. The clarification of factors that determine the etiology of MSI-H ovarian tumors are relevant to up to one-fifth of patients who have this deadly disease, hence these data may serve to advance clinical practice in several areas, including risk stratification, behavioral modification, and eventually have therapeutic relevance.