Ovarian Cancer and Mismatch Repair Deficiency

描述（由申请人提供）：卵巢癌在美国女性的癌症发病率和癌症死亡率中排名第五，并且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，大多数癌症都被视为一种疾病，治疗方法基于分期和分级。数据显示，对治疗的反应可能会有所不同，这取决于癌症的遗传病因。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带来更具体的治疗方案。 参与遗传性和散发性癌症发病机制的最明确的分子途径之一涉及错配修复（MMR）途径，其导致微卫星不稳定性（MSI）。MSI可能由两种遗传因素（即：MMR基因中的种系突变，包括MLH 1、MSH 2和MSH 6）和表观遗传（即：MLH 1启动子超甲基化）机制。本研究的目的是量化错配修复基因引起的卵巢肿瘤的比例，并描述这组肿瘤的特征。我们通过遗传基础对卵巢癌进行分类的能力为改善癌症预防和高危妇女筛查、基于分子标记的诊断和预后以及开发个性化治疗提供了希望。 迄今为止，只有少数卵巢癌MMR的小型研究已经进行，没有一个是基于人群的。这部分是由于难以招募大量具有代表性的卵巢癌患者。拟议的研究之所以可行，只是因为通过使用现有的三项北美人口研究的数据和样本，已经获得了广泛的资源，这些研究代表了迄今为止北美大多数人口病例。这项研究将包括2200例发生在莫菲特癌症中心、杜克综合癌症中心和多伦多大学的上皮性卵巢癌患者，并将是世界上此类患者的最大收集。将对所有卵巢癌受试者的石蜡包埋肿瘤样本进行分析，以进行MSI检测并研究MMR基因蛋白表达。在MSI-H状态或MMR基因蛋白表达缺失的样本中，将研究表观遗传（MLH 1启动子高甲基化）和遗传（生殖系MMR突变）。 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，行为改变，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.