Clonal intratumor heterogeneity of promoter hypermethylation in breast cancer by MS-MLPA

Moelans, Cathy B.; Groot, Jolien S. de; Pan, Xun; Wall, Elsken van der; Diest, Paul J. van

doi:10.1038/modpathol.2013.207

Cited by 19 publications

(18 citation statements)

References 22 publications

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“…The presence of hypomethylated and hypermethylated clones in various ovarian tumor samples may be associated with the presence of normal stromal cells, tumor cells at various stages of progression towards tumorigenesis, or populations of tumor cells subject to clonal evolution. This observation is in accordance with genetic or epigenetic intratumoral heterogeneity, as previously observed in colorectal (22), breast (23) and ovarian (24) cancer.…”

Section: Discussionsupporting

confidence: 76%

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

et al. 2016

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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...

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Section: Discussionsupporting

confidence: 76%

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

et al. 2016

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“…Quantitative methods for measuring mITH highlighted a high frequency of mITH across cancer types (Aggerholm et al, 1999; Korshunova et al, 2008; Moelans et al, 2014; Stirzaker et al, 1997; Varley et al, 2009). However, it remained difficult to compare the relative degree of mITH due to the lack of standardized methods and thresholds for calling mITH.…”

Section: Ith Of Dna Methylation At Individual Genesmentioning

confidence: 99%

Intratumoral Heterogeneity of the Epigenome

et al. 2016

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Investigation into intratumoral heterogeneity (ITH) of the epigenome is in a formative stage. The patterns of tumor evolution inferred from epigenetic ITH and genetic ITH are remarkably similar, suggesting widespread co-dependency of these disparate mechanisms. The biological and clinical relevance of epigenetic ITH are becoming more apparent. Rare tumor cells with unique and reversible epigenetic states may drive drug resistance, and the degree of epigenetic ITH at diagnosis may predict patient outcome. This perspective presents these current concepts and clinical implications of epigenetic ITH, and the experimental and computational techniques at the forefront of ITH exploration.

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“…Aberrant methylation of the CDH13 gene has been reported in many cancers, including non-small cell lung cancer [35], breast cancer [36], gastric cancer [37], and colorectal carcinoma [38]. However, the potential of CDH13 gene methylation to be a biomarker for bladder cancer has not yet been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of CDH13 promoter methylation as a biomarker for bladder cancer: a meta-analysis

et al. 2016

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BackgroundMethylation of the tumor suppressor gene H-cadherin (CDH13) has been reported in many cancers. However, the clinical effect of the CDH13 methylation status of patients with bladder cancer remains to be clarified.MethodsA systematic literature search was performed to identify eligible studies in the PubMed, Embase, EBSCO, CKNI and Wanfang databases. The pooled odds ratio (OR) and the corresponding 95 % confidence interval (95 % CI) was calculated and summarized.ResultsNine eligible studies were included in the present meta-analysis consisting of a total of 1017 bladder cancer patients and 265 non-tumor controls. A significant association was found between CDH13 methylation levels and bladder cancer (OR = 21.71, P < 0.001). The results of subgroup analyses based on sample type suggested that CDH13 methylation was significantly associated with bladder cancer risk in both the tissue and the urine (OR = 53.94, P < 0.001; OR = 7.71, P < 0.001; respectively). A subgroup analysis based on ethnic population showed that the OR value of methylated CDH13 was higher in Asians than in Caucasians (OR = 35.18, P < 0.001; OR = 8.86, P < 0.001; respectively). The relationships between CDH13 methylation and clinicopathological features were also analyzed. A significant association was not observed between CDH13 methylation status and gender (P = 0.053). Our results revealed that CDH13 methylation was significantly associated with high-grade bladder cancer, multiple bladder cancer and muscle invasive bladder cancer (OR = 2.22, P < 0.001; OR = 1.45, P = 0.032; OR = 3.42, P < 0.001; respectively).ConclusionOur study indicates that CDH13 methylation may play an important role in the carcinogenesis, development and progression of bladder cancer. In addition, CDH13 methylation has the potential to be a useful biomarker for bladder cancer screening in urine samples and to be a prognostic biomarker in the clinic.Electronic supplementary materialThe online version of this article (doi:10.1186/s12894-016-0171-5) contains supplementary material, which is available to authorized users.

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Clonal intratumor heterogeneity of promoter hypermethylation in breast cancer by MS-MLPA

Cited by 19 publications

References 22 publications

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

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

Intratumoral Heterogeneity of the Epigenome

Clinical significance of CDH13 promoter methylation as a biomarker for bladder cancer: a meta-analysis

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