High possibility of hepatocarcinogenesis in HBV genotype C1 infected Cambodians is indicated by 340 HBV C1 full-genomes analysis from GenBank

Channarena Chuon,Keiko Katayama,Sheikh Mohammad Fazle Akbar,Shintaro Nagashima,Junko Tanaka,Chikako Yamamoto,Ko Ko,Junko Matsuo,Kazuaki Takahashi,Sirany Hok

doi:10.1038/s41598-019-48304-z

Channarena Chuon, Keiko Katayama + Show 8 more

Open Access

https://doi.org/10.1038/s41598-019-48304-z

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Abstract

Approximately 75% of hepatocellular carcinomas (HCC) occur in Asia; core promoter mutations are associated with HCC in HBV genotype C, the dominant genotype in Cambodia. We analyzed these mutations in Cambodian residents and compared them with HBV full genomes registered in GenBank. We investigated the characteristics of 26 full-length HBV genomes among 35 residents positive for hepatitis B surface antigen in Siem Reap province, Cambodia. Genotype C1 was dominant (92.3%, 24/26), with one case of B2 and B4 each. Multiple mutations were confirmed in 24 Cambodian C1 isolates, especially double mutation at A1762T/G1764A in 18 isolates (75.0%), and combination mutation at C1653T and/or T1753V and A1762T/G1764A in 14 isolates (58.3%). In phylogenetic analysis, 16 of 24 isolates were located in the cluster with Laos, Thailand, and Malaysia. In 340 GenBank-registered C1 strains, 113 (33.2%) had combination mutation amongst which 16.5%, 34.2%, and 95.2% were found in ASC, chronic hepatitis, and liver cirrhosis (LC)/HCC respectively (P < 0. 001). Mutations were abundantly found in 24 Cambodian C1 isolates, and 340 C1 strains from GenBank showed mutation in genotype C1 brings high possibility of LC/HCC occurrence. Therefore, we suggest that Cambodian people infected with HBV genotype C1 have high possibility of hepatocarcinogenesis.

Highlights

Liver cancer is the second most common cause of cancer-related deaths worldwide and was estimated to cause nearly 746,000 deaths in 2012 (9.1% of all cancer-related deaths that year)[1]
We found that the prevalence of hepatitis B surface antigen (HBsAg) was 4.6% and that genotype C was dominant among adults in Cambodia[21]
Despite the high prevalence of hepatitis B virus (HBV) infection and high mortality from hepatocellular carcinomas (HCC) in Cambodia, only few reports have been published on the molecular characterisation of HBV genomes in this country, and only three complete genomic sequences have been reported[23,24,25]

Summary

Introduction

Liver cancer is the second most common cause of cancer-related deaths worldwide and was estimated to cause nearly 746,000 deaths in 2012 (9.1% of all cancer-related deaths that year)[1]. Hepatocellular carcinoma (HCC) accounts for more than 90% of cases of primary liver cancer[2] and chronic hepatitis B virus (HBV) infection is the leading cause of liver diseases evolving into liver cirrhosis and HCC3,4. 60% of HCC is associated with HBV, whereas 20% is related to hepatitis C virus[5] in Africa and Asia. HBV genotypes B and C are dominant in Asia, and genotype C plus core mutations in the HBV genome are associated with higher risk of HCC than genotypes A, B, and D6–8. Double mutation in the basal core promoter (A1762T/G1764A) of HBV genotype C was commonly found as an independent risk factor for the development of HCC9–11. Mutations at C1653T and/or T1753V and A1762T/G1764A in Enhancer II/basal core promoter were reported to be associated with HCC in 1999 compared with other liver disease statuses[13]. We used 340 full genomes of genotype C1 registered in GenBank for comparison

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