Endometrial carcinoma is the most common pelvic gynecologic malignancy. Methods for effective selection of patient at risk for metastasis, improved treatment for metastatic endometrial carcinoma and reliable predictive markers for response to new targeted therapeutics are urgently needed. This project is an international prospective multicenter study of tumor tissue aiming to facilitate implementation of molecularly based targeted therapy amongst women with endometrial carcinoma. The focus on methods to d etect lymph node metastases and aggressive disease trough studies of molecular markers in curettage specimens and functional imaging by MRI and FDG-PET, will potentially reduce side effects from extensive lymph node removal among low-risk patients. Furthe r, we focus on molecular alterations in endometrial cancer that can potentially be targeted. We have recently sequenced 129 tumor related genes in primary endometrial cancers, 90 of which are in the receptor tyrosine kinase pathway, with several mutations identified. Amongst these, we have further studied novel FGFR2 mutations in endometrial carcinomas and found them to be oncogenic and drug-sensitive. (Dutt,Salvesen et al. Proc Natl Acad Sci 2008). We have also found that gene expression profiles identif y an aggressive subtype of endometrial carcinoma associated with amplification of PIK3CA and PI3 kinase signature overexpression (AACR, late breaking news, 2008, Salvesen et al. revised manuscript submitted PNAS 2008). We want to expand these studies to s equence 2000 genes in collaboration with Broad Institute/Harvard and to validate the clinical significance of these findings in the prospective clinical trial we have initiated. Effects of new molecular targeted treatment in endometrial cancer cell lines based on their molecular profile will be studied. Finally we plan to design and initiate prospective treatment trials for new targeted therapy based on the results.