Molecular Genetic Basis for Gynecologic Neoplasias

该项目的目标是了解女性生殖道肿瘤中存在的分子遗传缺陷，包括子宫内膜癌和卵巢癌、子宫肉瘤和子宫平滑肌瘤（纤维瘤）。相关的研究涉及其他癌症的分子遗传学分析，这些癌症可能具有一些共同的激素方面，如乳腺癌或前列腺癌。在确定与子宫内膜癌病理生物学相关的癌基因和抑癌基因方面取得了重大进展。特别是，我们已经确定了PTEN脂质磷酸酶在这种癌症类型中的主要作用。许多子宫内膜癌不含PTEN、P53、KRAS 2等基因突变或微卫星不稳定表型（MSI）。微卫星不稳定性是大多数子宫内膜癌中MLH1基因表观沉默的结果，MSI表明其发展部分由表观遗传现象介导。重要的努力将被导向了解什么表观遗传变化的特点，各种类型的子宫内膜癌。与这一概念相关的是鉴定显示改变的mRNA或蛋白质水平的基因，其最终是表观遗传现象的结果。子宫肿瘤的全球mRNA和蛋白质表达谱将是该项目的主要重点。

The goals of this project involve understanding the molecular genetic defects present in neoplastic conditions of the female genital tract, including endometrial and ovarian carcinoma, uterine sarcoma and uterine leiomyoma (fibroids). Related studies involve molecular genetic analyses of additional cancers that may share some common hormonal aspects such as the breast or prostate. Significant progress has been made in defining the relevant oncogenes and tumor suppressor genes involved in the pathobiology of endometrial carcinoma. In particular, we have defined a major role for the PTEN lipid phosphatase in this cancer type. Many endometrial cancers do not contain mutation of genes such as PTEN, P53, KRAS2 or display the microsatellite instability phenotype(MSI). Microsatellite instability is the result of epigenic silencing of the MLH1 gene in most endometrial cancers with MSI suggesting there development is in part mediated by epigenetic phenomena. Significant effort will be directed towards understanding what epigenetic changes characterize the various types of endometrial cancer. Related to this concept is the identification of genes which display altered mRNA or protein levels which are ultimately a consequence of epigenetic phenomena. Global mRNA and protein expression profiling of uterine neoplasias will be a major focus of this project.