The studies on the methylation of promoter of tumor suppressor genes have produced some promising opportunities in clinical practise, giving the chance for a new biomarker in ovarian cancer. Methylation of TUSC3 (tumer suppressor candidate 3) promoter is leading to reduce expression of the gene and significantly affect the development and prognosis of ovarian cancer.
Epithelial ovarian cancer is the most common fatal cancer in gynecology and the fourth most frequent cause of cancer related deaths among women in industrialized countries. The reason of this is the fact that over 75% of patients with ovarian cancer is diagnosted in advanced clinical stage.
Patients with advanced ovarian cancer undergo surgery as well as platinum-based and taxane-based chemotherapy. Regardless of the progress in surgical and medical treatment in the past decades, the prognosis for women with advanced ovarian cancer remains unsatisfactory.
Gene TUSC3, originally named N33 was identified in the 8p22 region as a gene potentially inhibiting the development of prostate cancer. TUSC3 shows high sequence similarity with Ost3p, subunit complex of N-linked glycosylation of proteins in Saccharomyces cerevisiae (yeast species), suggesting an analogous function in mammalian cells. Modifications of proteins involved in N-linked glycosylation are some features of carcinogens such as invasiveness or metastatic potential. According to Pils D et al. studies the expression of a gene located in the 8p22 region can be regulated by promoter methylation. It is worth noting that this study did not include other possibilities of TUSC3 regulation by expression, such as the deletion of the region 8p22, which occurs in the case of prostate cancer and pancreatic cancer.
Hypermethylation of TUSC3 promoter on mRNA was tested in ovarian cancer cell lines using the polymerase chain reaction (PCR). 102 ovarian tumor samples were obtained from patients undergoing radical surgery. However, 20 samples of normal tissue derived from patients who underwent ovariectomy, nonetheless there was no cancer found. The results indicate that methylation of TUSC3 promoter was observed in 30 of the 102 ovarian cancer tissues (29.4%). However, it was not observed in the control group. TUSC3 promoter methylation in the primary ovarian cancer significantly correlated with decreased mRNA expression compared to the normal, healthy tissue, suggesting that the mechanism of promoter methylation influences the silencing of gene expression in ovarian cancer TUSC3. Statistical analysis showed no significant association between promoter methylation of TUSC3 parameters such as patient age, tumor grade (G) or the strongest predictors like FIGO stage and response to chemotherapy.
The results show that patients who came to TUSC3 gene promoter methylation had a significantly shorter progression-free survival (RR, 5.14; p=.001) and overall survival rates (RR, 2.23; p=.012). Patients who had tumors with TUSC3 promoter methylation had median progression-free survival of 11.1 months, compared with 24.6 months in the group where there was no methylation. Methylation of TUSC3 promoter is therefore predictive of progression-free survival and overall survival for patients with ovarian cancer.
After reconstitution in vitro gene TUSC3 scientists observed reduction of tumor cell proliferation and reduction in binding to extracellular matrix. Not only may the TUSC3 loss lead to the development of cancer, but it can also facilitate the adhesion of cancer cells by N-glycosylation. The loss of TUSC3 can also intraperitoneally promote metastasis.
In a study conducted by Pils D et al. TUSC3 gene plays an important role in the development and prognosis of ovarian cancer. The reduction of its expression by promoter methylation of this gene have a significant impact on the deterioration of prognosis in patients with ovarian cancer and is an important prognostic factor.
Written by: Anna Brzozowska MD, PhD, Magdalena Idziak MD
Source:
Pils D, Horak P, Vanhara P, Anees M, Petz M, Alfanz A, Gugerell A, Wittnger M, Gleiss A, Auner V, Tong D, Zeillinger R, Braicu EI, Sehouli J, Krainer M. Methylation Status of TUSC3 Is a Prognostic Factor in Ovarian Cancer. Cancer. 2013;119:946-54.
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