Promoter methylation and downregulated expression of the TBX15 gene in ovarian carcinoma

Abstract

Abstract. TBX15 is a gene involved in the development of mesodermal derivatives. As the ovaries and the female reproductive system are of mesodermal origin, the aim of the present study was to determine the methylation status of the TBX15 gene promoter and the expression levels of TBX15 in ovarian carcinoma, which is the most lethal and aggressive type of gynecological tumor, in order to determine the role of TBX15 in the pathogenesis of ovarian carcinoma. This alteration could be used to predict tumor development, progression, recurrence and therapeutic effects. The study was conducted on 80 epithelial ovarian carcinoma and 17 control cases (normal ovarian and tubal tissues). TBX15 promoter methylation was first determined by pyrosequencing following bisulfite modification, then by cloning and sequencing, in order to obtain information about the epigenetic haplotype. Immunohistochemical analysis was performed to evaluate the correlation between the methylation and protein expression levels. Data revealed a statistically significant increase of the TBX15 promoter region methylation in 82% of the tumor samples and in various histological subtypes. Immunohistochemistry showed an inverse correlation between methylation levels and the expression of the TBX15 protein. Furthermore, numerous tumor samples displayed varying degrees of intratumor heterogeneity. Thus, the present study determined that ovarian carcinoma typically expresses low levels of TBX15 protein, predominantly due to an epigenetic mechanism. This may have a role in the pathogenesis of ovarian carcinoma independent of the histological subtype. IntroductionOvarian cancer is the fourth most common type of cancer in the female genital tract, but has the highest mortality rate of all gynecological tumors. Ovarian carcinoma accounts for >90% of cases of ovarian cancer and may arise from relatively pluripotent cells of the coelomic epithelium or 'modified mesothelium' that covers the ovary (1). The coelomic epithelium is the mesodermal-derived epithelial lining of the intraembryonic coelom that invaginates to give rise to the mülllerian ducts, the primordia for the epithelia of the fallopian tube, the endometrium and the endocervix (1). There is now compelling evidence that certain carcinomas can also originate from the fallopian tubes and the endometriosis (1,2). Ovarian carcinoma are a heterogeneous group of neoplasms that exhibit a wide range of tumor morphologies and clinical manifestations (2). According to the World Health Organization classification, the most common tumor subtypes are serous, endometrioid and mucinous, and are characterized by their morphological resemblance to various mucosal tissues of the female reproductive tract (3). Cytogenetic and molecular analysis indicates that multiple genetic and epigenetic changes are involved in the pathogenesis of ovarian carcinoma (2,4); however, it remains unclear how these alterations lead to the development of ovarian cancer. Better understanding of the molecular mechanisms responsible for the diffe...

Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers

“…Normally, either a high or a low level of methylation should have been observed because the proportion of tumor cells in our samples was greater than 70%. This observation had already been made for analyses of methylation on a single gene by our group but also by others [ 27 , 28 ]. However, our study of 41 genes indicates that this phenomenon is quite general.…”

A Hybrid Ensemble Approach for Identifying Robust Differentially Methylated Loci in Pan-Cancers

“…Moreover, the corresponding upstream and downstream regions were located in a target gene, TBX15 . It has been demonstrated that TBX15 plays a vital role in multiple cancers, such as non–small cell lung cancer (Carvalho et al, 2013), thyroid cancer (Arribas et al, 2015), and ovarian carcinoma (Gozzi et al, 2016), and especially has been proved to be a methylation marker of prostate cancer (Kron et al, 2012). Moreover, Chelbi et al (2011) identified a region located in the distal promoter of the TBX15 that was differentially methylated and suggested that TBX15 might be involved in the pathophysiology of placental diseases.…”

Reduction of T-Box 15 gene expression in tumor tissue is a prognostic biomarker for patients with hepatocellular carcinoma

“…Recently, the association of TBX15 and cancer was demonstrated by the detection of breast cancer tissue-specific down-regulation of TBX15 , suggesting the use of TBX15 expression as a biomarker to facilitate accurate diagnosis and prognosis or as a predictive marker for treatment efficiency [ 28 ]. Further, the TBX15 promoter is hypermethylated in histological subtypes of ovarian cancer, and the methylation levels and expression of TBX15 inversely correlate [ 29 ]. Thus, hypermethylated TBX15 may serve as a potential biomarker for early detection of the induction and progression of ovarian cancer [ 29 ].…”