MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

描述（改编自研究者摘要）：大多数 在美国，妇科癌症的发病率和死亡率是由 子宫内膜癌和上皮性卵巢癌。 这些癌症是由一个多步骤、多基因的过程引起的， 和/或体细胞获得的突变。 本项目的长期目标 是为了确定最重要的分子遗传改变， 对这两种癌症的致瘤过程有贡献。 很可能 阐明与这些相关的基因突变谱， 癌症将有助于他们的预防和治疗，通过改善 风险评估、诊断、预后和治疗策略 关键的基因损伤 一个家族的生殖系突变 已经发现编码DNA错配修复蛋白的基因引起了 遗传性非息肉病性结直肠癌（HNPCC）综合征。 肿瘤 与这种综合征相关的特征是遗传不稳定性， 简单重复序列（微卫星）由突变引起 这些DNA修复基因之一的失活。 微卫星不稳定性 (MIS)在相当大比例的散发性肿瘤中也很明显， 构成HNPCC综合征，包括子宫内膜癌， 卵巢 本提案的具体目的是确定 散发性子宫内膜癌和卵巢癌MIS的特征， 为了解决这一现象的分子基础是 编码DNA修复的一个或多个基因的体细胞突变失活 蛋白质，或者，MIS也可能反映了表观遗传 与不适当的细胞分裂有关的现象。 为了评估MIS， 将对一组具有代表性的微卫星标记进行检查， 与正常组织DNA样本相比，肿瘤中的体细胞长度突变。 对于所有显示MIS的肿瘤和一组匹配的肿瘤， MIS的证据，将对基因进行突变分析 编码DNA修复蛋白，当突变时， 导入MIS。 研究细胞增殖的潜在作用 作为MIS的表观遗传原因，已知的雌激素反应性人类细胞 错配修复基因状态将用雌激素或促有丝分裂剂治疗 生长因子，并分析MIS的诱导。 辅助 与这些假设相关的数据将通过MIS定量生成 子宫内膜增生症的错配修复基因突变分析 标本，一种被认为代表I型前体的病变， 雌激素相关的子宫内膜癌 同样的分析也将 对子宫内暴露于 合成雌激素己烯雌酚 总之，这些数据应该 深入了解体细胞错配修复基因的相对作用 突变与异常细胞增殖在诱导MIS中的作用 妇科癌症

DESCRIPTION (Adapted from the Investigator's Abstract): The majority of gynecologic cancer incidence and mortality in the United States result from carcinoma of the uterine endometrium and epithelial ovarian carcinoma. These cancers arise from a multistep, multigenic process involving inherited and/or somatically acquired mutations. The long-term goals of this project are to define the most important molecular genetic alterations that contribute to the tumorigenic process for these two cancers. It is likely that elucidation of the spectrum of genetic mutations relevant to these cancers will contribute to their prevention and treatment through improved risk assessment, diagnostic, prognostic, and therapeutic strategies directed toward the critical genetic lesions. Germline mutations in a family of genes encoding DNA mismatch repair proteins have been found to cause the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The tumors associated with this syndrome are characterized by genetic instability in simple sequence repeats (microsatellites) resulting from mutational inactivation of one of these DNA repair genes. Microsatellite instability (MIS) is also evident in a significant percentage of sporadic tumors that constitute the HNPCC syndrome, including cancers of the endometrium and ovary. The specific aims of this proposal are to determine the extent and characteristics of MIS in sporadic endometrial and ovarian carcinomas, and to address the hypothesis that the molecular basis for this phenomenon is the somatic mutational inactivation of one or more genes encoding DNA repair proteins, or alternatively, that MIS may also reflect an epigenetic phenomenon related to inappropriate cell division. To assess MIS, a large, representative panel of microsatellite markers will be examined for evidence of somatic length mutations in tumor compared to normal tissue DNA samples. For all tumors that exhibit MIS and for a matched set of tumors with no evidence of MIS, a mutational analysis will be carried out on the genes encoding DNA repair proteins that, when mutated, have been implicated in the induction of MIS. To investigate the potential role of cell proliferation as an epigenetic cause of MIS, estrogen-responsive human cells of known mismatch repair gene status will be treated with estrogens or mitogenic growth factors in vitro, and analyzed for the induction of MIS. Ancillary data relevant to these hypotheses will be generated through MIS quantitation and mismatch repair gene mutation analyses of endometrial hyperplasia specimens, a lesion that is believed to represent a precursor to type I, estrogen-related endometrial carcinomas. The same analyses will also be performed on cervicovaginal adenocarcinomas from women exposed in utero to the synthetic estrogen diethylstilbestrol. Together, these data should provide insight into the relative roles of somatic mismatch repair gene mutations vs. aberrant cell proliferation in the induction of MIS in gynecologic cancers.