THE MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

妇科癌症仍然是这一地区妇女的主要健康问题。 每年约有25，000人死于此 问题. 不幸的是，这些肿瘤中的大多数仍然无法治疗， 诊断为晚期。 该项目的目的是 描述这组肿瘤的分子遗传学特征， 利用这些信息进行临床应用， 治疗、早期发现和预防试验。 我们对子宫内膜和卵巢标本进行了鉴定， 从良性到恶性的组织学谱中的突变， ras、p53和Rb基因。 对于子宫内膜癌，我们分析了 刮除标本。 ras基因的激活存在于非典型的 增生（14%）和子宫内膜癌（5%）; p53突变是 在大约15%的不典型增生和癌中发现。 这些研究将有助于确定分子遗传事件， 在子宫内膜癌的发生中起重要作用， 早期检测 卵巢肿瘤的评估显示，激活的ras基因被发现， 良性肿瘤（10%）和“LMP”肿瘤（30%），而卵巢癌（5- 10%）不。 此外，肿瘤抑制基因p53的突变 Rb和Rb在卵巢癌中出现（分别为48%和14%）， 不存在于LMP肿瘤中。 这表明这些肿瘤是离散的 生物实体。 我们现在通过检查143来扩展这些结果 来自一项大型前瞻性试验的晚期卵巢癌标本 (GOG#111）p53基因突变和 HER2/neu. 未来的项目将研究p53突变的价值， 卵巢癌的预后或早期检测标记物， 检查大量的早期卵巢癌。 这将 涉及从GOG#95中表征早期卵巢癌， HER 2/neu、p53和EGFR的表达。 最后，为了确定卵巢癌的潜在新标志物和基因， 在其发病机制中，恶性卵巢上皮细胞正在被 与使用差分显示技术的良性对应物相比。 差异表达的基因将被分离、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 problem. Unfortunately, most of these tumors remain untreatable when diagnosed in the advanced stage. 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, early detection, and prevention trials. We have characterized endometrial and ovarian specimens which span the histologic spectrum from benign to malignant for mutations in the ras, p53 and Rb genes. For endometrial 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. These studies will help to identify the molecular genetic events that are important in the genesis of endometrial cancer and their use for the its early detection. Evaluation of ovary 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 suggested that these tumors are discrete biologic entities. 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 overexpression of HER2/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. This will involve characterizing early ovarian cancers from GOG#95 for the expression of HER2/neu, p53 and EGFR. 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.