DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer

Letelier, Pablo; Brebi, Priscilla; Tapia, O.; Roa, Juan Carlos

doi:10.1186/1868-7083-4-11

Cited by 36 publications

(47 citation statements)

References 78 publications

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“…While our samples solely comprised formalin-fixed and paraffin-embedded tissue, Andresen et al included fresh frozen tissue samples, too [16]. In a previous study using the same CC series, both sample materials were compared and methylation frequencies of CDO1 , ZSCAN18 , SFRP1 , and DCLK1 were found to be generally lower in FFPE specimens than in the fresh frozen sample set while modern sensitive techniques may overcome this observation [29]. …”

Section: Discussionmentioning

confidence: 99%

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Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

et al. 2016

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BackgroundBiliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC.MethodsRelative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival.Results SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865–0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631–0.873).Conclusions SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0299-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Promoter hypermethylation, in particular, has been linked to transcriptional silencing of tumor suppressor genes, thus enabling neoplastic cells to proliferate without restriction [15]. In BTC and its precursor lesions, these epigenetic alterations can be detected with possible valuable clinical implications [16–29]. …”

Section: Introductionmentioning

confidence: 99%

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

et al. 2016

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“…The epigenetic alterations affecting TSGs involved in regulation pathways, cell cycle control, cell adhesion and extracellular matrix degradation, seem to have an important role to play in gallbladder carcinogenesis. Further, determining DNA methylation patterns would allow them to be used as biomarkers for the early detection, diagnosis, prognosis and/or therapeutic selection in GBC and should be a subject of intense research [70].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Changes in Carcinogenesis of Gallbladder

Tewari

Agarwal

Mishra

et al. 2013

Indian J Surg Oncol

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Gallbladder cancer (GBC) is a lethal and a common malignancy affecting mostly females. There are restricted high incidence pockets across the world and in northern India highest incidence of GBC is reported from the Gangetic belt. The etiology of this disease remains largely unknown though several risk factors have been stated. The genetic aberrations in GBC involving mutations in tumor suppressor genes and oncogenes have been reported in literature. However, there is scarcity of data regarding epigenetic changes that may also be involved in gallbladder carcinogenesis. This review attempts to summarize our current understanding of the epigenetic changes in GBC.

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“…For example, MF = 0.2 meant 20% (5 out of 25 cases) were simulated from the AR(1) model with E = 2 (methylated group) and 80% (20 out of 25 cases) were from E = 0 (unmethylated group). In reality, MF0.4 was often found in previous methylation studies [34], [35].…”

Section: Methodsmentioning

confidence: 85%

A Novel Method for Identification and Quantification of Consistently Differentially Methylated Regions

et al. 2014

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Advances in biotechnology have resulted in large-scale studies of DNA methylation. A differentially methylated region (DMR) is a genomic region with multiple adjacent CpG sites that exhibit different methylation statuses among multiple samples. Many so-called “supervised” methods have been established to identify DMRs between two or more comparison groups. Methods for the identification of DMRs without reference to phenotypic information are, however, less well studied. An alternative “unsupervised” approach was proposed, in which DMRs in studied samples were identified with consideration of nature dependence structure of methylation measurements between neighboring probes from tiling arrays. Through simulation study, we investigated effects of dependencies between neighboring probes on determining DMRs where a lot of spurious signals would be produced if the methylation data were analyzed independently of the probe. In contrast, our newly proposed method could successfully correct for this effect with a well-controlled false positive rate and a comparable sensitivity. By applying to two real datasets, we demonstrated that our method could provide a global picture of methylation variation in studied samples. R source codes to implement the proposed method were freely available at http://www.csjfann.ibms.sinica.edu.tw/eag/programlist/ICDMR/ICDMR.html.

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DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer

Cited by 36 publications

References 78 publications

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

Epigenetic Changes in Carcinogenesis of Gallbladder

A Novel Method for Identification and Quantification of Consistently Differentially Methylated Regions

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