Aberrant DNA methylation profile in cholangiocarcinoma

Huang, Li; Frampton, Gabriel; Lang, Liang; DeMorrow, Sharon

doi:10.4291/wjgp.v1.i2.23

Cited by 16 publications

(11 citation statements)

References 74 publications

(71 reference statements)

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“…ICC often arises in the background of chronic inflammation such as primary sclerosing cholangitis (PSC) which provides survival signals to the tumor (the contribution of the inflammatory microenvironment and epigenetics is reviewed in [47]). The cyclin-dependent kinase inhibitor p16 is frequently silenced by epigenetic modifications and was proposed as a prognostic marker associated with dismal outcome in patients with PSC [48].…”

Section: Alterations In the Epigenome In The Process Of Cholangiocarcmentioning

confidence: 99%

Genetic profiling of intrahepatic cholangiocarcinoma

Andersen¹,

Thorgeirsson²

2012

Current Opinion in Gastroenterology

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Purpose of review Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. Recent findings In comparison with other cancers genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. Summary We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single gene studies will also be discussed.

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Section: Alterations In the Epigenome In The Process Of Cholangiocarcmentioning

confidence: 99%

Genetic profiling of intrahepatic cholangiocarcinoma

Andersen¹,

Thorgeirsson²

2012

Current Opinion in Gastroenterology

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“…Studies evaluating patterns of DNA methylation in primary liver cancers have mostly focused on gene‐specific DNA methylation, so far. An aberrant gene‐specific DNA methylation leading to the inactivation of specific tumor‐suppressor genes through promoter hypermethylation has been recognized in HCC and in CC as an important mechanism of tumorigenesis. Studies focusing on global DNA methylation and hydroxymethylation status in primary liver cancers are few, and little or almost no data are available on the relationship with such epigenetic signatures and clinical outcome in terms of survival rate.…”

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confidence: 99%

Global DNA methylation and hydroxymethylation differ in hepatocellular carcinoma and cholangiocarcinoma and relate to survival rate

et al. 2015

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In addition to DNA methylation, hydroxymethylation of DNA is recognized as a novel epigenetic mark. Primary liver cancers, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), are highly prevalent but epigenetically poorly characterized, so far. In the present study we measured global methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) in HCC and CC tissues and in peripheral blood mononuclear cell (PBMC) DNA to define mCyt and hmCyt status and, accordingly, the survival rate. Both mCyt and hmCyt were measured by a liquid chromatography/tandem mass spectrometry method in neoplastic and homologous nonneoplastic tissues, i.e., liver and gallbladder, and in PBMCs of 31 HCC and 16 CC patients. Content of mCyt was notably lower in HCC than in CC tissues (3.97% versus 5.26%, respectively; P < 0.0001). Significantly reduced mCyt was also detected in HCC compared to nonneoplastic tissue (3.97% versus 4.82% mCyt, respectively; P < 0.0001), but no such difference was found for CC versus homologous nonneoplastic tissue. Hydroxymethylation was significantly decreased in HCC versus nonneoplastic liver tissue (0.044 versus 0.128, respectively; P < 0.0001) and in CC versus both liver and gallbladder nonneoplastic tissue (0.030 versus 0.124, P 5 0.026, and 0.030 versus 0.123, P 5 0.006, respectively). When the survival rate was evaluated according to mCyt PBMC content by Kaplan-Meier analysis, patients with mCyt 5.59% had a significantly higher life expectancy than those with mCyt <5.59% (P 5 0.034) at a follow-up period up to 48 months. Conclusion: A significant DNA hypomethylation distinguishes HCC from CC, while DNA hypohydroxymethylation characterizes both HCC and CC, and a PBMC DNA mCyt content 5.59% relates to a favorable outcome in primary liver cancers. (HEPATOLOGY 2015;62:496-504) M ethylation and hydroxymethylation of DNA are major epigenetic marks in human DNA consisting of modification of cytosines, respectively, as 5-methylcytosine (mCyt) and 5-hydroxymethylcytosine (hmCyt) in the dynamic processes of methylation and demethylation of DNA involved in the regulatory mechanisms of gene expression. [1][2][3] Methylation of DNA is the main epigenetic feature of mammalian DNA involved in several physiological processes through the transcriptional regulation of gene expression and chromatin conformational configuration 4 but also in pathologic conditions such as cancer disease development and progression. 5 Aberrant DNA methylation is an almost universal finding in cancer, where a global DNA hypomethylation, leading

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“…7 Anecdotal promoter hypermethylation of several tumor suppressor genes including RASSF1A, APC, CDKN2A, CDH1, DAPK1, FHIT, and MLH1 has been associated with CC; however, the degree of methylation and associated detection sensitivity and specificity varied between different studies. [8][9][10][11] These studies were restricted to candidate gene approaches using methylation-specific polymerase chain reaction (PCR) or array-based screening of limited target panels. To date, no attempt has been made to identify aberrant gene methylation and alterations of specific regulatory pathways in human CC on a global scale.…”

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confidence: 99%

Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway

et al. 2013

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The molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We performed a genome-wide analysis for aberrant promoter methylation in human CCs. We profiled 10 intrahepatic and 8 extrahepatic CCs in comparison to non-neoplastic biliary tissue specimens, using methyl-CpG immunoprecipitation (MCIp) combined with whole-genome CpG island arrays. DNA methylation was confirmed by quantitative mass spectrometric analysis and functional relevance of promoter hypermethylation was shown in demethylation experiments of two CC cell lines using 5-aza-2 0 deoxycytidine (DAC) treatment. Immunohistochemical staining of tissue microarrays (TMAs) from 223 biliary tract cancers (BTCs) was used to analyze candidate gene expression at the protein level. Differentially methylated, promoter-associated regions were nonrandomly distributed and enriched for genes involved in cancer-related pathways including Wnt, transforming growth factor beta (TGF-b), and PI3K signaling pathways. In CC cell lines, silencing of genes involved in Wnt signaling, such as SOX17, WNT3A, DKK2, SFRP1, SFRP2, and SFRP4 was reversed after DAC administration. Candidate protein SFRP2 was substantially down-regulated in neoplastic tissues of all BTC subtypes as compared to normal tissues. A significant inverse correlation of SFRP2 protein expression and pT status was found in BTC patients. Conclusion: We provide a comprehensive analysis to define the genome-wide methylation landscape of human CC. Several candidate genes of cancer-relevant signaling pathways were identified, and closer analysis of selected Wnt pathway genes confirmed the relevance of this pathway in CC. The presented global methylation data are the basis for future studies on epigenetic changes in cholangiocarcinogenesis. (HEPATOLOGY 2014;59:544-554)

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Aberrant DNA methylation profile in cholangiocarcinoma

Cited by 16 publications

References 74 publications

Genetic profiling of intrahepatic cholangiocarcinoma

Genetic profiling of intrahepatic cholangiocarcinoma

Global DNA methylation and hydroxymethylation differ in hepatocellular carcinoma and cholangiocarcinoma and relate to survival rate

Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway

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