The Molecular Genetics of Gynecologic Cancers

妇科癌症仍然是这个国家女性的一个主要健康问题，每年约有25,000人死于这一问题。这个项目的目的是描述这组肿瘤的分子遗传学特征，并最终将这些信息用于临床应用，合理设计治疗和预防试验。我们对子宫内膜、宫颈和卵巢标本进行了鉴定，这些标本涵盖了从良性到恶性的组织学谱，以检测ras、p53、细胞周期蛋白依赖性激酶抑制物、FHIT和Rb基因的突变以及微卫星不稳定性。对于子宫内膜癌，我们分析了刮宫标本：在非典型增生(14%)和子宫内膜癌(5%)中发现了激活的ras基因；在大约15%的非典型增生和癌中发现了p53突变。P15、p16和p18基因异常在子宫内膜癌中很少见。FHIT基因在宫颈癌及其前驱病变中异常，但在子宫内膜癌和卵巢癌中正常。这些研究应该有助于确定在子宫内膜癌和子宫颈癌的发生中起重要作用的分子遗传学事件，并将其用于早期检测。对卵巢肿瘤的评估显示，在良性(10%)和“LMP”肿瘤(30%)中发现激活的ras基因，而在卵巢癌(5-10%)中没有发现。此外，肿瘤抑制基因p53和Rb的突变在卵巢癌中发生(分别为48%和14%)，但在LMP肿瘤中不存在。这表明卵巢癌和LMP是离散的生物实体。此外，p15、16、18基因异常和微卫星不稳定性在这两种肿瘤中都极为罕见。P27在良性肿瘤和交界性肿瘤中表达正常，在恶性卵巢肿瘤中表达降低。此外，表达降低与肿瘤分期有关。我们通过检查来自大型前瞻性试验(GOG#111)的143例晚期卵巢癌样本来扩展这些结果，以检测p53基因突变、p27和细胞周期蛋白E的表达以及HER/2/neu。结果表明，在晚期卵巢癌中，Cyclin E的高表达而不是p27的下调是一个不良的预后因素。未来的项目将通过检测大量早期卵巢癌、来自Second Look手术的样本以及卵巢癌女性的PAP涂片，来检验P53突变作为卵巢癌预后或早期检测标记的价值。最后，为了确定潜在的卵巢癌新标志物和在其发病机制中重要的基因，正在使用差异显示技术、代表性显示和微阵列对恶性卵巢上皮和良性卵巢上皮进行比较。作为该实验室和MSK之间的主任挑战合作资助的一部分，400个卵巢癌标本将利用cDNA微阵列进行分析，模式将与诸如生存、组织学和分期等临床特征相关。差异表达的基因将被分离、克隆和鉴定其在卵巢癌发展中的作用。我们目前正在计划一项预见性的第三阶段试验，以验证这些基因的预后价值。

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 have extended these results by examining 143 specimens of advanced ovarian cancer from a large prospective trial (GOG#111) for mutations in the p53 gene, expression of p27 and cyclin E and HER/2/neu. The results demonstarte that overexpression of cyclin E but not downregulation of p27 is a poor prognostic factor in advanced ovarian cancer. 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, representational display, and microarrays. As part of the Director's Challenge collaborative grant between this laboratory and MSK, 400 ovarian canecr specimens will be profiled utilizing cDNA microarrays and patterns will be correlated with clinical characteristics such as survival, histology , and stage.Genes which are differentially expressed will be isolated, cloned and characterized for their role in the development of ovarian cancer. We are presently planning a prospecitive phase III trial to validate thye prognostic value of these genes.