THE MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

“妇科癌症仍然是一个主要的健康问题 大约有25,000人死于 每年都有这个问题。该项目的目的是 描述这组肿瘤的分子遗传学特征， 最终合理利用这些信息进行临床应用， 设计治疗和预防试验。我们有特点 子宫内膜、宫颈和卵巢标本， 组织学谱从良性到恶性的突变， ras、p53、细胞周期蛋白依赖性激酶抑制剂、FHIT和Rb基因 微卫星不稳定性对于子宫内膜癌， 分析刮宫标本：激活ras基因被发现在 非典型增生（14%）和子宫内膜癌（5%）; p53 在大约15%的非典型增生中发现了突变 和癌。p15、p16和p18的缺失是罕见的， 子宫内膜癌FHIT基因在宫颈癌中异常 和它们的前驱病变，但在子宫内膜中表现正常， 卵巢癌这些研究应该有助于确定 在子宫内膜发生中重要的遗传事件 以及它们在早期检测中的用途。 对卵巢肿瘤的评估显示，激活的ras基因在卵巢癌中表达。 良性（10%）和“LMP”肿瘤（30%），而卵巢 癌（5-10%）则没有。此外，肿瘤中的突变 抑癌基因p53和Rb存在于卵巢癌中（48例， 14%），但不存在于LMP肿瘤。这 提示卵巢癌和LMP是离散的生物学行为， 实体.此外，p15，16，18和微卫星异常 不稳定性在这两种肿瘤中是极其罕见。p27 在良性和交界性肿瘤中表达正常，但在良性和交界性肿瘤中表达降低 卵巢恶性肿瘤。此外，表达减少 与肿瘤分期有关。我们现在扩展这些结果 通过检查143例晚期卵巢癌标本， 针对p53基因突变的大型前瞻性试验（GOG#111） p27和HER/2/neu的表达。未来项目将研究 p53突变作为预后或早期检测的价值 通过检测大量的早期卵巢癌细胞， 分期卵巢癌，第二次检查手术的标本， 卵巢癌患者的子宫颈抹片检查。最后，为了识别 卵巢癌的潜在新标志物及其重要基因 发病机制，恶性卵巢上皮细胞被比较，其 良性对应使用差异显示技术。基因 其差异表达将被分离、克隆并 其特征在于它们在卵巢癌的发展中的作用。"

"Gynecologic cancer remains a major health problem for women in this country with approximately 25,000 deaths annually attributed to this problme. The purpose of this project is to characterize the molecular genetics of this group of tumors and ultimately use that information for clinical application in rationally designing therapeutic and prevention trials. We have characterized endomentrial, cervical, and ovarian specimens which span the histiologic spectrum from benign to malignant for mutations in the ras, p53, cyclin dependent kinase inhibitors, FHIT and Rb genes and microsatellite instability. For endomentrial cancers, we have analyzed curettage specimens: activated ras genes are found in the atypical hyperplasias (14%) and endometrial carcinomas (5%); p53 mutations are found in approximately 15% of atypical hyperplasia and carcinomas. Abnormalities in p15, p16, and p18 are rare in endometrial cancers. The FHIT gene is abnormal in cervical cancers and their precursor lesions but appears normal in endometrial and ovarian cancers. These studies should help to identify the molecular genetic events which are important in the genesis of endometrial and carvical cancers and their use for their early detection. Evaluation of ovarian tumors revealed that activated ras genes are found in benign (10%) and ""LMP"" tumors (30%) while ovarian carcinomas (5-10%) do not. In addition, mutations in the tumor suppressor genes p53 and Rb occur in ovarian carcinomas (48 and 14% respectively) but are not present in LMP tumors. This suggests that ovarian carcinoma and LMP are descrete biologic entities. In addition, abnormalities in p15, 16, 18, and microsatellite instability are extremely rare in both of these tumors. p27 expression in normal in benign and borderline tumors but decreases in malignant ovarain neoplasms. In addition, decreased expression correlates with stage of tumor. We are now extending these results by examining 143 specimens of advanced ovarian cancer from a large prospective trial (GOG#111) for mutations in the p53 gene and expression of p27 and HER/2/neu. Future projects will examine the value of p53 mutations as a prognostic or an early detection marker in ovarian cancers by examining large numbers of early stage ovarian cancers, specimens from second look operations, and PAP smears from women with ovarian cancer. Finally, to identify potential new markers of ovarian cancer and genes important in its pathogenesis, malignant ovarian epithelium is being compared to its benign counterpart using differential display technology. Genes which are differentially expressed will be isolated, cloned and characterized for their role in the development of ovarian cancer."