Abstract 5181: Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

Abstract

Abstract Background: In 2014, it is estimated that there will be over 30,000 new cases of hepatocellular carcinoma (HCC) and an estimated 20,000 subjects will die of this disease in the U.S. alone. Risk factors include chronic HBV/HCV infections, cirrhosis, alcohol abuse, diabetes, and fatty liver disease. However, an important subset of HCC occurs in the absence of any such risk factors. We surveyed the genomic and transcriptomic landscape of this subset of HCC. Methods: We performed whole genome and transcriptome sequencing of 30 matched tumor and non-tumor liver samples from resections performed at Washington University School of Medicine. Somatic variants identified in this discovery set were extended to a set of 89 additional cases by custom capture sequencing for a total of 119 HCCs profiled. All data were processed through The Genome Institute's Genome Modeling System (GMS) to analyze for viral integrations, SNVs, Indels, CNVs, fusions, SVs, expression and differential expression. Results: We report here for the first time the unique landscape of somatic alterations of HCC arising in non-cirrhotic liver. We detected and validated over 3,010 SNVs and indels in coding regions and 2,390 fusion transcripts, as well as extensive copy number and expression changes. We identified a single undiagnosed HBV case with viral integration occurring at the TERT promoter. We also confirmed recent reports of a recurrent TERT promoter mutation (G1295228A) occurring in at least 56% of cases. Additional recurrent mutations were observed in previously reported genes such as CTNNB1, TP53, AXIN1, and ARID1A, along with an increased frequency of RB1 loss, novel recurrent mutations of APOB, fusions in NR1H4, and other alterations. These molecular features were tested for association with clinical variables and outcome. Pathway analysis of recurrently altered genes suggests that, in the absence of external factors, genomic aberrations in basic liver metabolism genes may promote malignant transformation to HCC. Citation Format: Obi L. Griffith, Yiing Lin, Malachi Griffith, Jasreet Hundal, Allison Regier, Robert Fulton, Elizabeth M. Brunt, Richard K. Wilson, William Chapman, Elaine R. Mardis. Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5181. doi:10.1158/1538-7445.AM2014-5181