Abstract A1-30: Integrated genomic analysis identified sequential molecular aberrations in stepwise progression from early to classical hepatocellular carcinomas
Authors: Midorikawa Yutaka , Yamamoto Shogo , Tatsuno Kenji , Ueda Hiroki , Tsuji Shingo , Nagae Genta , Takayama Tadatoshi , Aburatani Hiroyuki 
Published: November 2015

Early hepatocellular carcinoma (HCC) is defined as a very well differentiated liver cancer with the presence of stromal invasion to the remaining Glisson's triad within the tumor (carcinoma in situ), which consists of small hepatocytes with little cellular atypia but with structural atypia. Different from classical HCC, early HCC is macroscopically characterized by indistinct margins and clinically detected as hypovascular lesion by imaging modalities. When such small-sized precursor lesions reach 1.5 to 2.0 cm in diameter, less differentiated cancerous tissues arise within the tumor and develop, finally replacing the very well differentiated HCC. Thus, early HCC originates from chronic liver disease and develops into classical HCC in stepwise manner. 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 containing somatic mutations, gene expression, fusion events, and copy number aberrations were compared between two groups. In addition, integrating the molecular alterations from different methods, we distinguished genetic driver aberrations from by-chance changes that are not relevant to cancer genome and elucidated recurrent pathways responsible for initiation and progression in stepwise hepatocarcinogenesis. Expression profile of early HCC was different from that of classical HCC, and chromosomal aberrations, somatic mutations, and gene fusion events were significantly frequent in classical HCC. By exome sequencing, mutation of CTNNB1, CSMD3, AXIN1, COL11A1, TSC2, and ATM were often observed in both groups, while those of TP53, ARID2 and ALPK2 were significantly frequent in classical HCC. Integrated analysis showed that distinct expression profile in early HCC would define it as another molecular entity from classical HCC due to its different mutation pattern. Prevalence of somatic mutations of CTNNB1 and p53/RB pathway genes were common, while those of ARID2 and AKT/PI3K pathway genes were significantly frequent in classical HCC. Unexpectedly, WNT target genes were up-regulated only in classical HCC with CTNNB1 mutation, 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 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, 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%), 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%). Despite of driver genes mutation, their pathways are not aberrantly activated and therefore, early HCC is a precursor in accordance with clinical characteristics different from classical HCC.

Citation Format: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani. Integrated genomic analysis identified sequential molecular aberrations in stepwise progression from early to classical hepatocellular carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-30.