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Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to ␤-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and Ecadherin underexpression. Conclusion: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies. (HEPATOLOGY 2007;45:42-52.) H epatocellular carcinoma (HCC) is one of the most frequently occurring solid tumors worldwide and is the third-leading cause of death from cancer. 1 Cirrhosis of any origin and dysplastic regenerative nodules have long been considered the likely precursors of HCC because of their frequent association with HCC occurrence. 2,3 As in other solid tumors, a large number of genetic alterations accumulate during the carcinogenetic process. Some of these genetic alterations are specific to HCC etiological risk factors, particularly HBV infection, which can induce chromosome instability or insertional mutagenesis. 4 Among the genetic alterations unrelated to HCC risk factors, microsatellite allelotypes and comparative genomic hybridization (CGH) studies have demonstrated recurrent chromosome aberrations. 5 Altogether, the principal carcinogenetic pathways known to be deregulated in HCC are inactivation of TP53, 6 Wnt/wingless activation mainly through CTNNB1 mutations activating ␤-catenin-and AXIN1-inactivating mutations, 7-9 retinoblastoma inactivation through RB1 and CDKN2A promoter methylation and rare gene mu-

Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery. National and international societies, as well as governing boards, should become involved in the goal of establishing training standards and credentialing, to ensure consistent standards and clinical outcomes.