Cyclin E dysregulation and chromosomal instability in endometrial cancer.

Deregulation of cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), has been associated with a broad spectrum of human malignancies. Yet the mechanism linking abnormal cyclin E expression to carcinogenesis is largely unknown. The gene encoding the F-box protein hCdc4, a key component of the molecular machinery that targets cyclin E for degradation, is frequently mutated in endometrial cancer, leading to deregulation of cyclin E expression. Here we show that hCDC4 gene mutation and hyperphosphorylation of cyclin E, a parameter that usually correlates with hCDC4 mutation, have a strong statistically significant association with polypoidy and aneuploidy in endometrial cancer. On the contrary, elevated expression of cyclin E by itself was not significantly correlated with polyploidy or aneuploidy when tumors of similar grade are evaluated. These data suggest that impairment of cell cycle regulated proteolysis of cyclin E may be linked to carcinogenesis by promoting genomic instability.

Methylation status and expression of human telomerase reverse transcriptase in ovarian and cervical cancer.

OBJECTIVES: Activation of telomerase, the enzyme that synthesizes the telomere ends of linear chromosomes, has been implicated in human cell immortalization and cancer cell pathogenesis. The expression pattern of human telomerase reverse transcriptase (hTERT), the telomerase catalytic subunit gene, is correlated with telomerase activity. The promotor region of the hTERT gene has been located in a CpG island and may therefore be regulated, at least in part, by DNA methylation. The potential for methylation-mediated regulation of hTERT gene expression in ovarian and cervical cancer tissue has not been investigated up to now. The aim of this study was to investigate the expression and methylation pattern of hTERT in ovarian and cervical cancer tissue and their correlation with clinicopathological features and outcome of the disease. METHODS: A total of 223 tissues were analyzed for hTERT methylation using MethyLight: 65 patients with cervical cancer and 124 with ovarian cancer were studied. The control group consisted of 20 normal ovarian tissues and 14 normal cervical tissues. Quantitative hTERT expression analysis was carried out in a subgroup of patients using real time PCR. RESULTS: hTERT expression was statistically significantly higher in ovarian and cervical cancer tissue in comparison to normal tissue. While methylation of hTERT in cervical cancer was significantly more frequent in comparison to normal cervical tissue, the difference between ovarian cancer and normal ovarian tissue was not significant. No correlation was detected between hypermethylation of hTERT and hTERT mRNA expression. Both ovarian cancer and normal ovary showed an increase in hTERT methylation with increasing age. hTERT expression was not correlated with prognosis, whereas cervical and ovarian cancer patients with unmethylated hTERT had significantly better overall survival. CONCLUSION: At least in some tumor entities, hTERT methylation is a function of age and is associated with a poorer outcome, irrespective of hTERT expression.