LIVER, PANCREAS, AND BILIARY TRACT Genetic Alterations Associated With Hepatocellular Carcinomas Define Distinct Pathways of Hepatocarcinogenesis PIERRE LAURENT–PUIG,* PATRICIA LEGOIX,* OLIVIER BLUTEAU,* JACQUES BELGHITI,‡ DOMINIQUE FRANCO,§ FREDERIC BINOT,* GENEVIÈVE MONGES,i GILLES THOMAS,* PAULETTE BIOULAC–SAGE,¶ and JESSICA ZUCMAN–ROSSI*

Background & Aims: To evaluate how characterization of genetic alterations can help in the elucidation of liver carcinogenesis pathways, 137 tumors were analyzed. Methods: High-density allelotype, p53, Axin1, and b-catenin gene mutations were determined. Alterations were analyzed according to clinical parameters. Results: Tumors could be divided into 2 groups according to chromosome stability status. In the first group, demonstrating a chromosome stability, b-catenin mutation associated with chromosome 8p losses were frequently found as the single genetic alterations. b-catenin mutations were associated with large tumor size and with negative hepatitis B virus status. In the second group, demonstrating a chromosome instability, the most frequent allelic losses were on chromosome 1p, 4q, 6q, 9p, 13q, 16p, 16q, and 17p; Axin1 and p53 were frequently mutated. All of these alterations, except losses on 6q and 9p, were associated with hepatitis B virus infection. P53 mutations, 17p, 13q losses, and a high value of the fractional allelic loss index were associated with poor differentiated tumors, independently of risk factors. Finally, in the whole series, chromosome 9p and 6q losses were associated with poor prognosis. Conclusions: Two main pathways defined by genetic alterations show different risk factors and clinical characteristics. Furthermore, loss of chromosome 9p or 6q is an independent prognostic indicator.