Promoter methylation and loss of coding exons of the fragile histidine triad (FHIT) gene in intrahepatic cholangiocarcinomas

Foja, Sabine; Goldberg, M.; Schagdarsurengin, Undraga; Dammann, Reinhard; Tannapfel, Andrea; Ballhausen, Wolfgang G.

doi:10.1111/j.1478-3231.2005.01174.x

Cited by 31 publications

(34 citation statements)

References 30 publications

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“…Other HIT proteins such as Hint1 and Fhit have been reported to be down-regulated in tumors by methylation of their promoter. 16,33,34 Reduced expression of tumor suppressors in cancer can also be accounted by loss of heterozygosity. In hepatocellular carcinoma, loss of heterozygosity on chromosome 9p is not rare 35 and is associated with a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Hint2, A Mitochondrial Apoptotic Sensitizer Down-Regulated in Hepatocellular Carcinoma

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Hint2, A Mitochondrial Apoptotic Sensitizer Down-Regulated in Hepatocellular Carcinoma

et al. 2006

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“…Chain Reaction (MSP) and Combined Bisulphite Restriction Analysis (COBRA) DNA was prepared from tissue specimens and subjected to sodium bisulfite modification as described elsewhere [Foja et al, 2005]. We added 3 M of sodium bisulfite, pH 5 (Sigma, Taufkirchen, Germany), to one mg of denatured DNA followed by incubation at 551C for 16-18 hr.…”

Section: Methylation-speci¢c Polymerasementioning

confidence: 99%

Different genetic pathways in the development of periocular sebaceous gland carcinomas in presumptive Muir-Torre syndrome patients

et al. 2006

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Periocular sebaceous gland carcinomas (SGCs) occur in the eyelids either sporadically or as a phenotypic feature of Muir-Torre syndrome (MTS). In knockout mice mismatch-repair (MMR) defects or inactivation of the fragile histidine triad (FHIT) gene are associated with MTS-like signs, including SGC. To dissect the genetic alterations associated with microsatellite instability (MSI) and inactivation of the FHIT gene, we studied nine periocular SGC specimens from MTS patients. Immunohistochemistry was performed for FHIT, MSH2, MLH1, and MSH6. We assessed MSI as well as loss of heterozygosity (LOH) at the FHIT locus with polymorphic markers and genomic multiplex PCR. Epigenetic silencing was detected by methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA). Our analyses identified two SGCs with FHIT positivity and high-grade MSI, and seven cases with loss of FHIT and microsatellite stability (MSS). MSI correlated with loss of MSH2 and MLH1 immunostaining. Loss-of-function mechanisms affecting the FHIT gene were identified as intragenic deletions eliminating the coding exons 5 and 6 on one hand, and complete biallelic methylation of the FHIT transcription regulatory region on the other hand. Germinal FHIT mutations as a predisposing factor for MTS were excluded in two index patients with cancer in three generations, including an FHIT-negative SGC. Our data suggest that either somatic inactivation of the FHIT gene associated with MSS or inactivation of the MMR system resulting in MSI contribute to the development of periocular SGCs in presumptive MTS.

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“…This promoter region hypermethylation has been shown to be associated with a poor clinical outcome. The DNA methylation frequencies of other genes related to cell cycle regulation, including p14 ARF [28, 32], p15 INK4b [28], p73 [28] and Ras association domain family 1A (RASSF1A) [26, 28, 33, 34], as well as their chromosomal locations are shown in table 1.…”

Section: Epigenetic Alterations In Ccamentioning

confidence: 99%

“…The DNA methylation frequencies including retinoic acid receptor-β2 (RARβ2; function: cell growth and differentiation) [28], glutathione S-transferase pi 1 (GSTP1; function: drug/xenobiotic metabolism) [28], fragile histone triad (FHIT; function: purine metabolism) [33], blunt protein (BLU; function: unknown) [37], methylated in tumor (MINT; function: unknown) [1, 12, 25, 31, 32] as well as their chromosomal locations are shown in table 1.…”

Section: Epigenetic Alterations In Ccamentioning

confidence: 99%

Epigenetic Alterations in Cholangiocarcinoma-Sustained IL-6/STAT3 Signaling in Cholangio- carcinoma due to SOCS3 Epigenetic Silencing

Isomoto¹

2009

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Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium, characterized by its typically late clinical presentation and lack of effective therapeutic modalities. Chronic inflammatory conditions, including primary sclerosing cholangitis, liver fluke infestation and hepatolithiasis, are listed in the risk factors, but for most cases of CCA the cause is unknown. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations including promoter hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes hypermethylated in CCA to date and their putative roles in cholangiocarcinogenesis. Among genes hypermethylated, we found the CpG island hypermethylation in suppressor of cytokine signaling 3 (SOCS3) gene promoter in CCA. Interleukin-6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT3) activation are aberrantly sustained in CCA cells, resulting in resistance to apoptosis. SOCS3 controls the IL-6/STAT3 signaling pathway by a classic feedback loop. Indeed, SOCS3 epigenetic silencing is responsible for sustained IL-6/STAT3 signaling in CCA. These findings provide new perspectives for epigenetic therapy to restore SOCS3 in this cancer.

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Promoter methylation and loss of coding exons of the fragile histidine triad (FHIT) gene in intrahepatic cholangiocarcinomas

Abstract: Epigenetic silencing of the FHIT tumor suppressor gene is a novel inactivation mechanism to be considered in the development of intrahepatic cholangiocarcinomas. However, a statistically significant inverse correlation between K-Ras activation and RASSF1A inactivation was not found.

Cited by 31 publications

References 30 publications

Hint2, A Mitochondrial Apoptotic Sensitizer Down-Regulated in Hepatocellular Carcinoma

Hint2, A Mitochondrial Apoptotic Sensitizer Down-Regulated in Hepatocellular Carcinoma

Different genetic pathways in the development of periocular sebaceous gland carcinomas in presumptive Muir-Torre syndrome patients

Epigenetic Alterations in Cholangiocarcinoma-Sustained IL-6/STAT3 Signaling in Cholangio- carcinoma due to SOCS3 Epigenetic Silencing

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