Invited Lecture(JSH)
Fri. November 6th   9:00 - 9:40   Room 8: Portopia Hotel Main Building Kairaku 1+2
Invited Lecture11
 HBV DNA integrations in the HCC genomes: Providing a new classification and a new circulating tumor biomarker
Pei-Jer Chen
Hepatitis Research Center, National Taiwan University Hospital
Chronic HBV infections account for 60% of HCC worldwide. In addition to common mutations of telomerase promotors, p53 and beta-catenin, HBV-related HCCs harbor a unique mutation, namely, HBV integrations in their genomes. Decades ago, around 90% of HBV-related HCC were found with integrated HBV DNA by southern blotting and recently by whole genome sequencing. In contrast, HBV integration occurs only in 0.1-0.5% of virus-infected hepatocytes. A rapid enrichment of HBV integration in HCC strongly indicated its contribution to carcinogenesis.
Recently we developed a HBV-capture-sequencing platform for rapidly characterizing the HBV integrations in large number of B-related HCC. From about 200 such HCCs, we found about 170 cases with HBV integrations, with a mean of 4 integrations per HCC. As the HBV integration must happen in virus infection stages and as early events driving cancer formation, we are interested in studying their roles in carcinogenesis. Interestingly, the HBV-related HCC can be classified by HBV integration sites and telomerase promoter mutation into four exclusive groups. The first group HCCs (about 30%) contain HBV integration into the telomerase gene promoter. The second group, about 25%, contain point mutation in the telomerase promoter. The third group, about 15%, harbor HBV integration in the exon2 or 3 of MLL4 gene (one histone methyl transferase gene). The fourth group do not contain the three mutations. We are now studying the clinical outcomes, histology features, and gene expression profiles and responses to current molecular target or immune-oncology therapies.
The HBV integration event in individual HCC has been shown random, therefore unique to each HCC. Therefore, the integration sites in the genomes can be used as a signature for the clonality or presence of individual HCC. Such viral integration sites can be released into circulation as part of circulating cell-free tumor DNA (ctDNA). Our HBV-capture-sequencing platform is thus applied to characterize the virus-host junction fragments from the ctDNA in HBV-related HCC. We succeeded in discovering such viral-host junction ctDNAs in patients with HCC about 5 cm. With droplet digital PCR, we can detect such vhDNA in patients with HCC about 2-3 cm in diameter. Currently, the HBV-capture sequencing platform undergoes clinical trials in monitoring the HCC recurrence and clonality in the post-operative HCC. Hopefully, it can be applied to monitor the tumorigenesis in chronic hepatitis B patients in the near future.
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