The Molecular Genetics of Gynecologic Cancers

妇科癌症仍然是我国妇女的一个主要健康问题，每年约有25 000人死于这一问题。该项目的目的是表征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，以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表征，这些标本跨越了ras、p53、周期蛋白依赖性激酶抑制剂、FHIT和Rb基因的突变和微卫星不稳定性，从良性到恶性的组织学谱。对于子宫内膜癌，我们分析了刮宫标本：在不典型增生（14%）和子宫内膜癌（5%）中发现了活化的ras基因；在大约15%的非典型增生和癌中发现P53突变。p15、p16和p18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是异常的，但在子宫内膜癌和卵巢癌中是正常的。这些研究应该有助于确定在子宫内膜癌和宫颈癌发生过程中重要的分子遗传事件，并将其用于早期检测。卵巢肿瘤的评估显示，在良性肿瘤（10%）和“LMP”肿瘤（30%）中发现了激活的ras基因，而卵巢癌（5-10%）则没有。此外，肿瘤抑制基因p53和Rb的突变发生在卵巢癌中（分别为48%和14%），但不存在于LMP肿瘤中。这表明卵巢癌和LMP是独立的生物实体。此外，p15、16、18异常和微卫星不稳定在这两种肿瘤中都极为罕见。P27在卵巢良性和交界性肿瘤中表达正常，而在卵巢恶性肿瘤中表达降低。此外，表达的减少与肿瘤的分期有关。我们通过对来自一项大型前瞻性试验（gog# 111）的143例晚期卵巢癌标本进行p53基因突变、p27、细胞周期蛋白E和HER/2/neu的表达，扩展了这些结果。结果表明，cyclin E过表达而p27不下调是晚期卵巢癌的不良预后因素。未来的项目将通过检查大量早期卵巢癌、二次检查手术标本和卵巢癌妇女的PAP涂片，来检验p53突变作为卵巢癌预后或早期检测标志物的价值。最后，为了确定卵巢癌的潜在新标志物和在其发病机制中重要的基因，利用差异显示技术、代表性显示和微阵列技术将恶性卵巢上皮与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例卵巢癌标本将利用cDNA微阵列进行分析，并将模式与生存、组织学和分期等临床特征相关联。差异表达的基因将被分离、克隆和表征其在卵巢癌发展中的作用。我们目前正在计划一项前瞻性的III期试验，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.