Exploration of genomic differences between early and advanced endometrial endometrioid carcinoma

• Main Authors: Chang, Shing-Jyh, 張幸治
• Other Authors: Chang, Dah-Tsyr
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/79796459330424769207

博士 === 國立清華大學 === 分子與細胞生物研究所 === 100 === It has been recognized that cancer cells acquire characters reminiscent of those of normal stem cells, and the degree of stem cell gene expression correlates with patient prognosis. Lgr5(+) or CD133(+) epithelial stem cells (EpiSCs) have recently been identified and these cells are susceptible to neoplastic transformation. It is unclear, however, whether genes enriched in EpiSCs also contribute in tumor malignancy. Endometrial endometrioid carcinoma (EEC) is a dominant type of the endometrial cancers and is still among the most common female cancers. Clinically endometrial carcinoma is classified into four FIGO (International Federation of Gynecology and Obstetrics) stages by the degree of tumor invasion and metastasis, and the survival rate is low in patients with higher stages of tumors. Identifying genes shared between advanced tumors and stem cells will not only unmask the mechanisms of tumor malignancy but also provide novel therapeutic targets. To identify EpiSC genes in late (stages III-IV) EECs, a molecular signature distinguishing early (stages I-II) and late EECs was first characterized to delineate late EECs at the genomics level. ERBB2 and CCR1 were genes activated in late EECs, while APBA2 (MINT2) and CDK inhibitor p16 tumor suppressors were in early EECs. MAPK pathway was significantly up regulated in late EECs, indicating that drugs targeting this canonical pathway might be useful for treating advanced EECs. Immunohistochemistry (IHC) staining on another independent tissue set confirmed the overexpression of ERBB2 (HER2/neu) oncogene in advanced EECs. A six-gene mini-signature was further identified to differentiate early from advanced EECs in both training and testing datasets. Advanced, invasive EECs possessed a clear EpiSC gene expression pattern, explaining partly why these tumors are more malignant. This study provides new insights into the pathogenesis of EECs and reveals a previously unknown link between adult stem cells and the histopathological traits of EECs. Shared EpiSC genes in late EECs may contribute to the stem cell-like phenotypes shown by advanced tumors and hold the potential of being candidate therapeutic targets and novel prognosis biomarkers. The possibility of repurposing existing clinical drugs against ERBB2 for the treatment of EECs is awaited to be evaluated.