Overexpression of p21 and MDM2 characterizes serous borderline ovarian tumors

Palazzo, Juan; Monzon, Federico A.; Burke, Melissa; Hyslop, Terry; Dunton, Charles J.; Barusevicius, Alan; Capuzzi, David M.; Kovatich, Albert J.

doi:10.1053/hupa.2000.7641

Cited by 30 publications

(30 citation statements)

References 32 publications

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“…The LMP-G1 group of tumors was characterized by the near-uniform expression of genes such as MUC5B, c-fos and p21/WAF-1 (CDKN1A) (Figure 1b). Although high p21 expression has previously been reported in LMP tumors (Palazzo et al, 2000), we were surprised to see high expression of CDKN1A in G1 tumors, which suggested decreased cellular growth capacity of these invasive carcinomas. Using Euclidean distance as a measure of similarity, we searched for genes whose expression was highly correlated with CDKN1A ( Figure 3a).…”

Section: Comparative Genomic Hybridization (Cgh) Analysis Demonstratecontrasting

confidence: 63%

“…Conversely, CDKN1A mRNA is weakly expressed or absent in G2-G3 carcinomas and low or absent levels of this protein have been correlated with high-grade, advanced FIGO stage, primary residual tumor and poor OS. Low expression is also inversely correlated with high proliferative capacity and p53 positivity (Anttila et al, 1999;Palazzo et al, 2000;Vassilopoulos et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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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.

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Section: Comparative Genomic Hybridization (Cgh) Analysis Demonstratecontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…Palazzo et al (2000) noted a similar lack of correlation between proliferation rate and the levels of p21 WAF1 in LMP tumours. The authors claimed that this finding was to be expected in tumours with a low proliferation index as well as in normal tissues and benign tumours.…”

Section: Discussionmentioning

confidence: 83%

“…The low Ki-67 levels in LMP tumours might indicate that most cells are still able to exit from the cell cycle into G 0 , as opposed to malignant tumours. Following this line of argument, this group of authors (Palazzo et al, 2000) attributed the lack of p21 WAF1 in non-cycling cells to degradation of the protein, once the cell has entered a cell cycle exit state.…”

Section: Discussionmentioning

confidence: 99%

Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications

et al. 2007

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Minichromosome maintenance proteins (MCM) have recently emerged as novel proliferation markers with prognostic implications in several tumour types. This is the first study investigating MCM-2 and MCM-5 immunohistochemical expression in a series of ovarian adenocarcinomas and low malignant potential (LMP) tumours aiming to determine possible associations with clinicopathological parameters, the conventional proliferation index Ki-67, cell cycle regulators (p53, p27 Kip1 , p21 WAF1 and pRb) and patients' outcome. Immunohistochemistry was applied in a series of 43 cases of ovarian LMP tumours and 85 cases of adenocarcinomas. Survival analysis was restricted to adenocarcinomas. The median MCM-2 and MCM-5 labelling indices (LIs) were significantly higher in adenocarcinomas compared to LMP tumours (Po0.0001 for both associations). In adenocarcinomas, the levels of MCM-2 and MCM-5 increased significantly with advancing tumour stage (P ¼ 0.0052 and P ¼ 0.0180, respectively), whereas both MCM-2 and MCM-5 increased significantly with increasing tumour grade (P ¼ 0.0002 and P ¼ 0.0006, respectively) and the presence of bulky residual disease (Po0.0001 in both relationships). A strong positive correlation was established between MCM-2 or MCM-5 expression level and Ki-67 LI (Po0.0001) as well as p53 protein (P ¼ 0.0038 and P ¼ 0.0500, respectively). Moreover, MCM-2 LI was inversely correlated with p27KipÀ1 LI (P ¼ 0.0068). Finally, both MCM-2 and MCM-5 were associated significantly with adverse patients' outcome in both univariate (X20 vs 420%, P ¼ 0.0011 and X25 vs o25%, P ¼ 0.0100, respectively) and multivariate (P ¼ 0.0001 and 0.0090, respectively) analysis. An adequately powered independent group of 45 patients was used in order to validate our results in univariate survival analysis. In this group, MCM-2 and MCM-5 expression retained their prognostic significance (Po0.0001 in both relationships). In conclusion, MCM-2 and MCM-5 proteins appear to be promising as prognostic markers in patients with ovarian adenocarcinomas.

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“…Owing to its close localisation with MDM2, an inhibitor of p53, the SAS oncogene is often associated with the amplification of MDM2 in human sarcomas (Meltzer et al, 1991). In ovarian cancer expression, MDM2 is more characteristic of serous LMP (Palazzo et al, 2000). A deeper analysis would be necessary to determine the potential involvement of SAS and MDM2 and their prognostic value in serous LMP cancer.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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In order to elucidate the biological variance between normal ovarian surface epithelial (NOSE) and epithelial ovarian cancer (EOC) cells, and to build a molecular classifier to discover new markers distinguishing these cells, we analysed gene expression patterns of 65 primary cultures of these tissues by oligonucleotide microarray. Unsupervised clustering highlights three subgroups of tumours: low malignant potential tumours, invasive solid tumours and tumour cells derived from ascites. We selected 18 genes with expression profiles that enable the distinction of NOSE from these three groups of EOC with 92% accuracy. Validation using an independent published data set derived from tissues or primary cultures confirmed a high accuracy (87 -96%). The distinctive expression pattern of a subset of genes was validated by quantitative reverse transcription -PCR. An ovarian-specific tissue array representing tissues from NOSE and EOC samples of various subtypes and grades was used to further assess the protein expression patterns of two differentially expressed genes (Msln and BMP-2) by immunohistochemistry. This study highlights the relevance of using primary cultures of epithelial ovarian cells as a model system for gene profiling studies and demonstrates that the statistical analysis of gene expression profiling is a useful approach for selecting novel molecular tumour markers.

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Overexpression of p21 and MDM2 characterizes serous borderline ovarian tumors

Cited by 30 publications

References 32 publications

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

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

Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications

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

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