Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions.

Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances

“…Although these mechanisms driving HCC are random, some spec genetic abnormalities or epigenetic regulations are inextricably linked to HCC [2 Thanks to the development of next-generation high-throughput sequencing technolo bio-information technology and proteomic analysis technology, we can understand molecular mechanism of HCC from the perspectives of the genome, epigenetics, transcriptome and proteome, and explore the gene expression patterns and epigene characteristics of tumor tissues and cells [3]. The discovery of novel mechanisms of vi carcinogenesis is critical, as these findings may ultimately lead to the development vaccination strategies and HCC treatment decisions, leading to personalized medicine reduce virus-mediated cancer mortality and improve the prognosis of HCC patie [2,26].…”

Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

“…In particular, the upregulated genes are involved in cell division, cell cycle, and proliferation. The most considerable genes hypomethylated on CpGs around their promoter are FANCB , KIF15 , KIF4A , ERCC6L , and UBE2C [ 81 ]. CDKN2A , a key regulator of G1 cell cycle arrest, is hypermethylated and inactivated in many cancer types [ 82 ].…”

Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1

“…Among them, TERT (telomerase reverse transcriptase) is the most frequently integrated gene [43,47,48], followed by MLL4 (Myeloid/lymphoid or mixed-lineage leukemia 4) [43,49]. FN1 (Fibronectin 1) [43,50], CCNE1 (Cyclin E1) [43,51] CCNA2 (Cyclin A2) [43,51] and ROCK1 (Rho-associated, coiled-coil containing protein kinase 1) [43,51] have also been reported. (For a more complete list of the integrated genes, please refer to the review of Lee et al [52].)…”

“…(For a more complete list of the integrated genes, please refer to the review of Lee et al [52].) These targeted genes for HBV integration usually are closely related to tumor progression and also are shown to be significantly enriched in cancer-related pathways [50,53]. In addition, integrated HBV DNA becomes a stable source for the production of truncated or mutated HBx and pre-S1/S2 proteins whose expression may also contribute to hepatocarcinogenesis [54].…”