Influence of some methylated hepatocarcinogenesis-related genes on the response to antiviral therapy and development of fibrosis in chronic hepatitis C patients

Abstract

Background/Aims: Epigenetics involved in multiple normal cellular processes. Previous research have revealed the role of hepatitis C virus infection in accelerating methylation process and affecting response to treatment in chronic hepatitis patients. This work aimed to elucidate the role of promoter methylation (PM) in response to antiviral therapy, and its contribution to the development of fibrosis through hepatocarcinogenesis-related genes. Methods: A total of 159 chronic hepatitis Egyptian patients versus 100 healthy control group were included. The methylation profile of a panel 9 genes (SFRP1, p14, p73, APC, DAPK, RASSF1A, LINE1, O6MGMT, and p16) was detected in patients' plasma using methylation-specific polymerase chain reaction (MSP). Results: Clinical and laboratory findings were gathered for patients with combined pegylated interferon and ribavirin antiviral therapy. Regarding the patients' response to antiviral therapy, the percentage of non-responders for APC, O6MGMT, RASSF1A, SFRP1, and p16 methylated genes were significantly higher versus responders (P<0.05). Of the 159 included patients, the most frequent methylated genes were SFRP1 (102/159), followed by p16 (100/159), RASSF1A (98/159), then LINE1 (81/159), P73 (81/159), APC (78/159), DAPK (66/159), O6MGMT (66/159), and p14 (54/159). A total of 67/98 (68.4%) cases of RASSF1A methylated gene (P=0.0.024), and 62/100 (62%) cases of P16 methylated gene (P=0.03) were associated with mild-degree fibrosis. Conclusions: To recapitulate, the PM of SFRP1, APC, RASSF1A, O6MGMT, and p16 genes increases in chronic hepatitis C patients, and can affect patients' response to antiviral therapy. The RASSF1A and P16 genes might have a role in the distinction between mild and marked fibrosis.

RASSF1A and p16 promoter methylation and treatment response in chronic hepatitis C genotype 1b patients treated with pegylated interferon/ribavirin

“…Aberrant methylation of RASSF1A and p16 was detected in 32.6% and 28.6% of the cases, respectively. The observed frequencies of methylation in our study fit into the percentages reported in previous studies, which range from 16.2% to 68.4% for RASSF1A [17,36,37] and from 23.5% to 62% for the p16 gene [34,37], depending on the stage of the disease. Existing literature data indicate that the methylation of p16 and RASSF1A gradually increases with disease progression, with the highest levels detected in HCC [8,18,[36][37][38][39].…”

“…The observed frequencies of methylation in our study fit into the percentages reported in previous studies, which range from 16.2% to 68.4% for RASSF1A [17,36,37] and from 23.5% to 62% for the p16 gene [34,37], depending on the stage of the disease. Existing literature data indicate that the methylation of p16 and RASSF1A gradually increases with disease progression, with the highest levels detected in HCC [8,18,[36][37][38][39]. The methylation status of RASSF1A or p16 was not related to host factors, such as fibrosis, age and gender of patients.…”

“…The methylation status of RASSF1A or p16 was not related to host factors, such as fibrosis, age and gender of patients. According to previous studies, it was reported that the methylation of both RASSF1A and p16 gene is associated with mild fibrosis [37], while such an association was observed for RASSF1A promoter methylation only [8]. The discrepancies in our and these results could be attributed to the small sample size (as in our study), or to different HCV genotypes that were analyzed, since both research groups analyzed genotype 4.…”

“…Therefore, the role of p16 should be further examined on a larger sample size. The predictive role of DNA methylation profiles of specific genes in CHC patients has not been well studied with only a few studies [8,12,37,43]. Existing literature data suggest that methylation of the RASSF1A and p16 genes was significantly related to the NR group of patients [8,37].…”

Screening, confirmation, and treatment rates of hepatitis C virus infection in a tertiary academic medical center in South Korea

“…fatty liver) might be a contributing factor, the results of our study might indicate that anti‐HCV positivity, either by overt infection or past infection, might be significantly associated with higher fibrotic burden, which is the major determinant of long‐term prognosis. The progressive effect of HCV infection in terms of the development of chronic liver disease, cirrhosis, hepatic decompensation, and HCC is well known in the literature, 16–18 and careful observation should be undertaken in patients with progressed liver disease considering the risk of liver cirrhosis and HCC even after successful antiviral treatment 6,19–22 . Therefore, appropriate referral to a gastroenterologist is necessary for patients testing positive for anti‐HCV antibodies to enable proper evaluation, treatment, and follow‐up, which might improve their long‐term prognosis 20,21 …”