演題抄録

FACO Symposium

開催概要
開催回
第53回・2015年・京都
 

Multiple Gene Expression Profile of Liver Cancer: Integrative Analysis

演題番号 : FS2-3

[筆頭演者]
Choi Jong Young:1,2 

1:Department of Internal Medicine, The Catholic University of Korea, Korea、2:Department of Internal Medicine, Seoul St. Mary's Hospital, Korea

 

Hepatocellular carcinoma(HCC) could be considered as an acquired genetic disorder defined by accumulation of somatic genetic alterations in HCC cells. Recent genomic integrated analysis confirmed several important signaling pathways in HCC.
First, telomere maintenance: 90% of human HCC harbor an increased telomere expression. Mechanisms include TERT promoter mutations(50-60%), TERT amplification(5-6%), and HBV insertion in TERT promoter(10-15%). Second, the Wnt/b-cathenin pathway is frequently activated in HCC by activating mutations of CTNNB1(11-37%), and inactivating mutations of AXIN1(5-15%), or APC(10%). Third, the P53-cell cycle is altered in half of HCC patients with frequent TP53 mutations(12-48%). RB pathway that control the progression from G1 to S phase is inactivated in HCC mainly by homozygous deletion of CDKN2A(2-12%) or RB1 mutations(3-8%). Fourth, epigenetic modifiers are recurrently altered in HCC, with inactivating mutations ARID1A(4-17%) and ARID2(5-18%). They belong to the chromatin remodeling gene family, encoding subunit of SW1/SNF complexes and are considered tumor suppressor genes. Fifth, activating mutations of NRF2 or inactivating KEAP1(5-15%) prevents proteasome degradation of NRF2. NRF2 dissociated from KEAP1 translocates to the nucleus and activates the transcription of antioxidant genes, which gives proliferative and survival advantages to tumor cells. Finally, the PI3k/AKT/mTOR and RAS/RAF/MAPK kinase pathways are activated(5-10%) by amplification of the FGF/CNND1 locus. Also, homogygous deletion of PTEN, an inhibitor of the PI3K/AKT/mTOR cascade, has been identified(1-3%).
Among the huge number of genes mutations in HCC genome, functional analysis is necessary to understand the consequences of tumorigenesis and develop targeted treatment. Data generated by massive parallel sequencing needs to be integrated with transcriptomic, methylome analysis, proteonomic, and metabolomic in order to capture the full complexity of HCC.

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