The role of CpG islands hypomethylation and abnormal expression of neuronal protein synuclein-gamma (SNCG) in ovarian cancer.

The synucleins are a family of small cytoplasmic proteins that are expressed predominantly in neurons. Recently, their expression has been found also in many human cancers. To understand the molecular mechanisms underlying the abnormal expression of SNCG in malignant ovarian tumors, in this study, we examined the methylation status of a CpG island located in exon 1 of SNCG gene in a panel of ovarian malignant tumors to determine if DNA methylation is related to clinical and histological tumor characteristics. SNCG mRNA expression in tumor samples was assessed by RT-PCR. Methylation status of SNCG gene was studied using methylation specific PCR (MSP). Study group included 43 ovarian carcinoma samples (40 primary and 3 metastatic). The expression of SNCG mRNA was detectable in 33 of 43 ovarian cancer cases (76.7%). There were no significant differences in the mRNA expression between serous or nonserous tumors. The presence of SNCG mRNA in tumor samples was not correlated with age and menopausal status of patients, also no correlation was found with clinical stage or histological grading of malignant tumors. In 29 of 43 (67.4%) cases of tumors unmethylated product of MSP amplification was present. In a group of SNCG mRNA-positive tumors there were 75.7% (25 of 33) cases with demethylated or hypomethylated exon 1 of SNCG. The differences between the groups were statistically significant (chi2 =4.46; p=0.034). Demethylation of SNCG was not related to clinical tumor stage (p>0.05), but it was strongly associated with tumor grading (chi2=6.66; p=0.035). Aberrant methylation of SNCG was more often seen in tumors of women after menopause (78.2% vs 55%). In postmenopausal women 18 of 33 (62.1%) tumor samples synuclein-gamma mRNA expression was found, however the differences were not statistically significant. No correlations between SNCG hypomethylation and patient age, clinical stage and tumor grading were found. In 9 of 43 samples (21%) both products of amplification with methylated or unmethylated primer sets were found. In all of these cases SNCG mRNA was present. SNCG mRNA is expressed in a substantial proportion of malignant ovarian tumors and demethylation is an important event in abnormal synuclein-gamma expression in most of these cases.