Hepatitis B virus (HBV) may drive oncogenesis of hepatocellular cancer (HCC) by preferentially inserting viral DNA into host cell genomic regions that are vulnerable to DNA mutations and rearrangements, according to a study published in Nature Communications.1

HBV promotes carcinogenesis by integrating viral DNA into the host genome, causing chromosomal instability and deregulating host gene expression. Until recently, the pattern of HBV integration was believed to be random, based on data obtained with polymerase chain reaction (PCR)-based methods and deep sequencing. More recently, recurrent sites of HBV insertions have been identified in a sizeable cohort of patients with HCC via next-generation sequencing.

The most common site of HBV integration is the telomerase reverse transcriptase gene (TERT), which may enhance an early clonal advantage in chronic HBV infections. However, the incidence of recurrent integration at these sites occurred in a minority of patients.

There is evidence that HBV integration also plays a role in the development of HCC, especially in patients without liver cirrhosis. Finally, men with chronic HBV infections are more likely to develop HCC than women, but the mechanisms to explain this observation have not been elucidated.

“The interaction between HBV integrants and human genome during HCC development remains largely unknown,” Hongyang Wang, MD, of the National Center for Liver Cancer in China, told Infectious Disease Advisor.

Dr Wang and colleagues characterized patterns of HBV integration into host genome using high-throughput viral integration detection (HIVID), which is more sensitive for assessing viral insertion than whole-genome sequencing. HIVID was performed on tumor and adjacent non-tumor samples from 426 patients with HBV-associated HCC.

HBV integration favored fragile and chromosomal repetitive regions that may confer a survival advantage in tumorigenesis.  A higher-than expected proportion of HBV insertion sites was found in proximity to telomeres, which are central for maintaining chromosomal stability.

Recurrent HBV integration sites were identified in TERT, as well as in numerous novel genes that may enhance oncogenesis or have tumor suppressive activity. HBV was also found to favor insertion into promoter regions, where gene transcription is initiated.

The occurrence of HBV integrations was much higher among men than women, particularly on chromosome 17, which contains many genes implicated in the development of HCC. Among both cirrhotic and non-cirrhotic patients, HBV integration patterns were similar and tended to affect genes that may be involved in oncogenesis or tumor suppression.

“By using the largest sample collection to date—at least 5 times larger than any previous study—and state-of-the-art HIVID, we have identified the largest series of HBV insertion sites reported to date,” Dr Wang said. “Our results have also provided the first evidence that HBV could integrate into host genome in a gender- and cirrhosis-dependent manner.”

“Our data suggest that HBV integration has a high potential to drive oncogenic transformation,” Dr Wang wrote.

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 Reference

  1. Zhao LH, Liu X, Yan HX, et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat Commun. 2016;7:12992. doi: 10.1038/ncomms12992.