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Progression of hepatocellular carcinoma (HCC) is a stepwise process that proceeds from preneoplastic lesions-including low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs)-to advanced HCC. The molecular changes associated with this progression are unclear, however, and the morphological cues thought to distinguish pre-neoplastic lesions from well-differentiated HCC are not universally accepted. To understand the multistep process of hepato-carcinogenesis at the molecular level, we used oligo-nucleotide microarrays to investigate the transcription profiles of 50 hepatocellular nodular lesions ranging from LGDNs to primary HCC (Edmondson grades 1-3). We demonstrated that gene expression profiles can discriminate not only between dysplastic nodules and overt carcinoma but also between different histological grades of HCC via unsupervised hierarchical clustering with 10,376 genes. We identified 3,084 grade-associated genes, correlated with tumor progression, using one-way ANOVA and a one-versus-all unpooled t test. H epatocelluar carcinoma (HCC) is one of the most common malignancies worldwide. The chronic hepatitis resulting from infection with hepatitis B virus or hepatitis C virus and exposure to carcinogens such as aflatoxin B1 are known as major risk factors for HCC. 1 Molecular investigations have recently found that genetic alterations of tumor suppressor genes or oncogenes such as p53, ␤-catenin, and AXIN1 might be involved in the progression to HCC, 2-4 but the frequency of these somatic mutations appears to be low in HCCs. Furthermore, it is unclear how these genetic changes reflect the clinical characteristics of the individual tumors. Therefore, the predominant molecular events underlying HCC in most patients remain unknown.Because HCC typically develops in close association with pre-existing cirrhosis, it is widely believed that a liver with cirrhosis may contain pre-neoplastic nodules that are in an intermediate stage between nonneoplastic regenerating nodules and overtly malignant HCC. 5,6 These nod-

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Ras proteins control signaling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. BRAF, which encodes a RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers. The activating mutation of BRAF is known to play a role in tumor development. As there have been no data on the BRAF mutation in stomach cancer, we analysed the genomic DNAs from 319 stomach carcinomas for the detection of somatic mutations of BRAF. Overall, we detected BRAF mutations in seven stomach carcinomas (2.2%). Five of the seven BRAF mutations involved Val 599, the previously identified hotspot, but the substituted amino acid (V599 M) was different from the most common BRAF mutation (V599E). The remaining two mutations involved a conserved amino acid (D593G). One tumor had both BRAF and KRAS mutations. This is the first report on BRAF mutation in stomach cancer, and the data indicate that BRAF is occasionally mutated in stomach cancer, and suggest that alterations of RAS pathway both by RAS and BRAF mutations contribute to the pathogenesis of stomach cancer.