THE MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

妇科癌症仍然是这个地区女性的主要健康问题。 每年约有25,000人死于此病 我有问题。这个项目的目的是描述分子的特征 这组肿瘤的遗传学，并最终利用这些信息 合理设计治疗和预防措施的临床应用 审判。 我们已经确定了子宫内膜、宫颈和卵巢标本的特征 从良性到恶性的组织学谱系中的突变 Ras、p53、细胞周期蛋白依赖性激酶抑制物和Rb基因及 微卫星不稳定。对于子宫内膜癌，我们已经分析了 刮宫标本：在非典型癌中发现激活的ras基因。 增生症(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。 P15、p16和p18基因异常在子宫内膜癌中很少见。这些 研究应该有助于确定哪些分子遗传事件是 子宫内膜癌的发生及其早期应用的重要意义 侦测。 对卵巢肿瘤的评估显示发现激活的ras基因。 良性(10%)和“LMP”肿瘤(30%)，而卵巢癌(5%-10%) 不。此外，肿瘤抑制基因P53和Rb的突变 发生于卵巢癌(分别为48%和14%)，但不存在 在LMP肿瘤中。这表明卵巢癌和LMP是相互独立的。 生物实体。此外，p15、16、18和 微卫星不稳定性在这两种肿瘤中都是极其罕见的。我们 现在正在通过检查143个高级样本来扩展这些结果 来自一项大型前瞻性试验(GOG#111)的卵巢癌基因突变 P53基因与HER/2/neu的过表达 未来的项目将研究P53突变作为预后或 卵巢癌早期检测标记物的大量检测 早期卵巢癌，来自Second Look手术的样本 卵巢癌患者的巴氏涂片。我们还将评估 FHIT基因在妇科癌症发生中的潜在作用 最后，确定潜在的卵巢癌新标记物和基因 恶性卵巢上皮在其发病机制中具有重要作用 与使用差异显示技术的良性对应物进行比较。 差异表达的基因将被分离、克隆和 以其在卵巢癌发展中的作用为特征。

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, 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. These studies should help to identify the molecular genetic events which are important in the genesis of endometrial cancer and their use for its 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. 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 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. We will also evaluate the potential role of the FHIT gene in the development of gynecologic cancers. 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.