Abstract 958: Early hepatocellular carcinoma as another entity from classical hepatocellular carcinoma by integrated genomic analysis
Authors: Midorikawa Yutaka , Yamamoto Shogo , Tatsuno Kenji , Ueda Hiroki , Tsuji Shingo , Nagae Genta , Sonoda Kotaro , Shibata Tatsuhiro , Covington Kyle R. , Creighton Chad J. , Sugitani Masahiko , Wheeler David A. , Takayama Tadatoshi , Aburatani Hiroyuki 
Published: August 2015

Abstract
Early hepatocellular carcinoma (HCC) is defined as a very well differentiated cancer containing Glisson's triad with stromal invasion of, which originates from chronic liver disease and develops into classical HCC with accumulation of genetic aberrations. To identify sequential genetic alterations in stepwise hepatocarcinogenesis, transcriptome and whole-exome sequences were performed on 47 early and 105 classical HCCs, and molecular aberrations were compared between the two groups. Integrated analysis of transcriptome and exome sequences showed that distinct expression profile in early HCC would define it as another molecular entity from classical HCC due to its different mutation pattern, and was more similar to the chronic liver disease rather than classical HCC. By exome sequence, prevalence of somatic mutations of WNT (25.5 vs 42.9%, P = 0.047), p53/RB pathway (31.9 vs 41.9%, P = 0.242), and methyltransferase genes (17.0 vs 20.0%, P = 0.665) was common, while those of SWI/SNF complexes (8.5 vs 27.6% P = 0.026) and AKT/PI3K pathway (8.5 vs 29.5%, P = 0.045) genes were significantly frequent in classical HCC. Unexpectedly, WNT target genes were up-regulated only in classical HCC with CTNNB1 mutation but not in early HCC, and even down-regulated in those with AXIN1 mutation. Similarly, cell cycle genes related with p53/RB pathway were up-regulated only in classical HCC. Taken together, despite of frequent mutations in CTNNB1 and TP53 genes in early HCC, additional mutational events such as SWI/SNF complexes and AKT/PI3K pathway will be required for transcriptional activation of downstream targets in HCC progression. Furthermore, transcriptome sequence showed that TERT is the most frequently up-regulated in early HCC by various mechanisms: recurrent gene fusion including 3 prime portion of TERT such as SLC12A7-TERT (8.5% vs 0%), focal gain of 5p15.33 (19.1 vs 12.3%), hepatitis B virus integration (2.1 vs 3.8%), and TERT promoter mutation (63.8 vs 59.0%). In total, at least one or more aberrations in chromosomal genetic aberrations occurred in early (85.1%) and classical (74.2%) HCCs. Taken together, frequent driver gene mutations and TERT gene up-regulation due to diverse kinds of mechanisms were elucidated by transcriptome and exome sequences in early HCC. On the other hand, despite of frequent mutations in CTNNB1 and TP53 in early HCC, additional mutational events will be required for transcriptional activation of downstream targets in HCC progression, which suggests that early HCC is not a real cancer but a precursor of liver malignancy in accordance with clinical characteristics.
Citation Format: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Kotaro Sonoda, Tatsuhiro Shibata, Kyle R. Covington, Chad J. Creighton, Masahiko Sugitani, David A. Wheeler, Tadatoshi Takayama, Hiroyuki Aburatani. Early hepatocellular carcinoma as another entity from classical hepatocellular carcinoma by integrated genomic analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 958. doi:10.1158/1538-7445.AM2015-958