Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential

Abstract

Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12 500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2-G3 groups of tumors was highly correlated to patient outcome (v 2 for equivalence of death rates ¼ 7.681189; P ¼ 0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular 'meta-signature' in human cancer, and underscore a number of cell-cycle-and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.

Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer

“…Gene expression of epithelial ovarian cancer C Le Page et al Interestingly, our LMP tumours showed the least distinct profile in comparison to NOSE (Figure 1), which correlates with the weak aggressive potential of these tumours and the favourable prognostic for the patient. The present results correlate well with recent attempts to distinguish LMP and solid malignant tumours using a microarray and gene profiling approach (Gilks et al, 2005;Meinhold-Heerlein et al, 2005;Ouellet et al, 2005). Here, we detected only a very small set of genes differentially expressed in LMP tumours.…”

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

“…Although a number of key molecules implicated in control of this vesicle transport chain, including DLK1 and MAP3K5, seem to be up-regulated in LMP tumors (versus highgrade invasive), the pathway has been mostly studied in the context of neuronal transport and axonal damage repair (64,65), and its relation to tumor pathobiology has not been explored. A high incidence of activating mutations in the RAS-MAPK pathway has commonly been found in LMP tumors (3,7,8,11,12), and we found either BRAF or KRAS mutations in the majority of LMP cases tested (59%, 79 of 134). We found BRAF mutations in 46% of serous LMP.…”

“…Overall, the results have suggested that LMP tumors follow a different process of cellular transformation compared with the majority of their invasive counterparts. One striking feature of LMP tumors is the high rate of KRAS and BRAF mutations, both of which are thought to act primarily through the canonical RAS-MAPK (RAS-RAF-MEK-ERK-MAP kinase) pathway (3,7,(10)(11)(12)(13). Furthermore, many serous LMP tumors have been reported to have wild-type p53 and functional p53 signaling (8,14).…”

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

“…We have previously shown that progressive paclitaxel resistance in vitro is associated with increasing IL-6 expression in ovarian cancer cell lines and showed that transfection of IL-6 (a Stat3 activating ligand) into some cell lines induced paclitaxel resistance [7,10]. Recently, several studies have demonstrated that Stat3 is highly activated in high-grade as well as recurrent drug resistant ovarian cancer tumor cells [8,18,22,25]. Constitutive activation of the Stat3 pathway has been shown to confer resistance to chemotherapy-induced apoptosis in epithelial malignancies [2].…”