Ovarian cancer classification: Lessons from morphology, molecules, and mice
Authors: Kathleen Cho
Journal: Clinical Cancer Research (2008)

PL03-01   Ovarian carcinomas are a heterogeneous group of neoplasms traditionally sub-classified based on type and degree of differentiation as assessed by light microscopy. Although the current clinical management of ovarian carcinoma largely fails to take this heterogeneity into account, it is becoming evident that each major histological type has characteristic genetic defects that deregulate specific signaling pathways in the tumor cells. Moreover, within the most common histological types, the molecular pathogenesis of low-grade versus high-grade tumors appears to be largely distinct. For example, low-grade serous carcinomas (characterized by frequent mutations of  KRAS  and  BRAF ), likely arise from serous borderline tumors, which in turn develop from benign serous cystadenomas. This stepwise tumor progression in the low-grade pathway contrasts with the rapid progression pathway of high-grade serous carcinomas (characterized by chromosomal instability and frequent  TP53  mutations), for which precursor lesions are not well recognized. High-grade serous carcinomas may arise from ovarian surface inclusions, peritoneal mesothelium, or the distal portion (fimbriae) of the fallopian tube. These carcinomas disseminate to pelvic and peritoneal organs early in their progression. Like their low-grade serous counterparts, low-grade endometrioid carcinomas are often associated with recognizable precursor lesions, such as endometriosis and/or benign endometrioid neoplasms. Low-grade endometrioid carcinomas frequently harbor mutations that constitutively activate PI3K/Pten and Wnt/β-catenin-dependent signaling. In contrast, high-grade endometrioid carcinomas typically lack PI3K/Pten and Wnt/β-catenin pathway defects and have frequent  TP53  mutations. The global gene expression profiles of high-grade endometrioid and serous carcinomas are quite similar to each other and largely distinct from the profiles of low-grade endometrioid, clear cell, and mucinous carcinomas.  Genetically engineered mouse models of each major subtype of ovarian cancer will undoubtedly prove useful for improving knowledge of ovarian cancer biology and for preclinical testing of novel therapeutic strategies. Significant progress has been made in developing histologic-type specific models of ovarian cancer. As noted above, defects in the PI3K/Pten and Wnt/β-cat signaling pathways often co-occur and likely cooperate in the development of some human endometrioid adenocarcinomas. Deregulation of these two pathways in the murine ovarian surface epithelium by conditional inactivation of the  Pten  and  Apc  tumor suppressor genes results in the formation of adenocarcinomas morphologically similar to human endometrioid adenocarcinomas with 100% penetrance, short latency, and rapid progression to metastatic disease. The biological behavior and gene expression patterns of the murine cancers resemble those of human ovarian cancers with comparable signaling pathway defects. Studies are underway to further develop the model as a tool for pre-clinical testing of therapies that target deregulated Wnt/β-catenin and PI3K/Pten signaling, which may ultimately lead to better clinical outcomes for women with ovarian cancer.