Abstract 559: Development of a novel approach to identify cancer drivers for hepatitis B virus-associated hepatocellular carcinoma

Infection with Hepatitis B virus (HBV) is a major etiology of hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Studies have shown that some cells infected with HBV contain integrated viral DNA, and integrated viral DNA has been observed more frequently in HCC than in non-HCC infected liver. Although integration occurs randomly throughout host chromosomes, recurrent integration sites have been reported. Interestingly, these integration sites are located in genes known to be involved in carcinogenesis. During HCC carcinogenesis, tumor cells undergo uncontrolled clonal expansion in which a particular integration junction will become dominant (or a major junction). We have adapted a method known as primer extension capture (PEC) to enrich integrated HBV DNA for next-generation sequencing (NGS) to detect these integration junctions that occur at low frequency. We next developed a novel program, “HccDriverFinder,” to identify major junctions, incorporate PubMed data mining for driver identification, detect HBV mutations (revealing a striking 98.8% HCC-linked mutations identified in cancer), and visualize integration events. By analyzing NGS data generated from 13 matched HCC and adjacent non-HCC tissue samples, we found specific integrations in known targets such as TERT and CCNE1, and uncovered new recurrent HBV integration sites in genes including CSAD and ABCC13 (both of which are reportedly linked with tumorigenesis). We have further optimized the PEC approach to enrich for the whole HBV genome and have applied it to urine DNA from 31 hepatitis, 27 cirrhosis, and 29 HCC patients for the potential of identifying HBV junctions in circulation. Our approach holds the promise of building a driver identification kit for HCC detection, drug development and precision medicine. Citation Format: SHIH-CHUN SHEN, Amy Jiaen Lu, John Caleb Shieh, Yih-Ping Su, Bilal Nasir, Ning Ling, Daryl T. Lau, Jamin D. Steffen, Fwu-Shan Shieh, Wei Song, Ying-Hsiu Su. Development of a novel approach to identify cancer drivers for hepatitis B virus-associated hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 559.