RESUMO
Cholangiocarcinoma (CCA) is the most common primary liver cancer in Northeastern Thailand where liver fluke infection is highly endemic. Although aberrant DNA methylation in CCA has been reported by several investigators, little is known regarding the associations between them. In the present study, the results obtained from our previously published methylation array were analyzed and 10 candidate genes involved in DNA repair [protein phosphatase 4 catalytic subunit (PPP4C)], apoptosis [runt related transcription factor 3 (RUNX3), interferon regulatory factor 4 (IRF4), ubiquitin Cterminal hydrolase L1 (UCHL1) and tumor protein p53 inducible protein 3 (TP53I3)], cell proliferation [cyclin D2 (CCND2) and Ras association domain family member 1 (RASSF1)], drug metabolism [aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and solute carrier family 29 member 1 (SLC29A1)] and angiogenesis [human immunodeficiency virus1 tat interactive protein 2 (HTATIP2)] were selected for quantification of their methylation levels in 54 CCA and 19 adjacent normal tissues using methylationsensitive highresolution melting. The associations between the methylation status of the individual genes and clinical parameters were statistically analyzed. High methylation levels were observed in UCHL1, IRF4, CCND2, HTATIP2 and TP53I3. The median methylation level of UCHL1 was 57.3% (range, 3.15 to 88.7%) and HTATIP2 was 13.6% (range, 7.5 to 36.7%). By contrast, low methylation of HTATIP2 and UCHL1 was identified in adjacent normal tissues. The methylation status of HTATIP2 and UCHL1 was associated with patients' overall survival. CCA patients with high methylation of HTATIP2 and low methylation of UCHL1 exhibited longer overall survival. In addition, multivariate Cox regression analysis demonstrated that UCHL1 methylation was an independent factor for CCA with hazard ratio of 1.81 (95% confidence interval, 1.013.25) in high methylation group. The combination of HTATIP2 and UCHL1 methylation status strongly supported their potential predictive biomarker in which patients with CCA who had high methylation of HTATIP2 and low methylation of UCHL1 showed longer overall survival than those with low HTATIP2 methylation and high UCHL1 methylation. In conclusion, the present study revealed the value of aberrant DNA methylation of HTATIP2 and UCHL1, which may serve as a potential predictive biomarker for CCA.
Assuntos
Acetiltransferases/genética , Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Ubiquitina Tiolesterase/genética , Acetiltransferases/metabolismo , Idoso , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Ciclina D2/genética , Ciclina D2/metabolismo , Metilação de DNA , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Fígado/patologia , Fígado/cirurgia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Ubiquitina Tiolesterase/metabolismoRESUMO
The prevalence of HBV and HCV infection among 295 cholangiocarcinoma (CCA) patients in northeast Thailand was analyzed. Hepatitis B surface antigen (HBsAg) was detected in 8.8% (26/295 cases) and antibodies to HCV (anti-HCV) in 2.7% (8/295 cases) of CCA cases. Screening for HBV DNA was performed in 15 of 26 HBV seropositive cases and genotypes could be determined in all 15. HBV genotypes C and B were detected in 73.3% (11/15 cases) and 26.7% (4/15 cases), respectively. HCV RNA was detected in 87.5% (7/8 cases) of anti-HCV positive cases. Specifically, 57.1% (4/7 cases) were HCV genotype 1a and 42.9% (3/7 cases) were HCV genotype 3a. The prevalence of infection and genotype distribution of both HCV and HBV among CCA in northeast Thailand is comparable to that in the general population, suggesting that HCV and HBV infections are, if at all, not serious risk factors for CCA.
