The Cancer Genomics Project focuses on comprehensive characterization of the cancer genome and aims to identify cancer-related genes, including potential therapeutic targets and biomarkers, and to clarify their alteration profiles contributing to the pathogenesis of cancer.

Whole-genomic chromosomal alteration profiles of 87 primary HCCs have been clarified by means of the high-density array-based comparative genomic hybridization (CGH) methodology, and novel homozygous deletions and chromosomal amplification were characterized ⁽¹²⁶⁾. Unsupervised clustering analyses based solely upon the chromosomal alteration patterns of the tumors revealed that HCCs could be divided into 2 major groups that were statistically significantly associated with pathological features, HBV/HCV infection of the background liver and clinical outcome of the patients. Further analyses of the clustered data revealed 6 subgroups characterized by pathognomonic chromosomal amplifications containing putative therapeutic targets, such as the RPS6KB1 gene (a signal transducer of the mTOR pathway). An in vitro experiment raised the possibility that rapamycin, an inhibitor of the mTOR pathway, would significantly inhibit the proliferative activity of HCC cells with amplification of 17q which contains the RPS6KB1 gene ⁽¹²⁶⁾.

The genome-wide expression profiles of lung adenocarcinomas were compared with the mutation status of EGFR, ERBB2, KRAS and BRAF. Gene expression signatures associated with the EGFR mutation status or the clinical outcome were identified. Integrated analysis of genetic and gene expression profiles aimed at delineating inherent oncogenic pathways in cancer will be valuable for discovering novel biomarkers and predicting clinical outcomes ⁽¹²⁷⁾.

Lung adenocarcinoma in the early stage is seen as a pure ground-grass opacity (GGO) on high-resolution computed tomography (HRCT). Mutational analysis of the EGFR and KRAS genes and immunohistochemical staining of the p53 protein were performed in 23 lung adenocarcinomas that were followedup by HRCT. EGFR mutations were frequently (74%) found in lung adenocarcinomas visualized as a GGO on HRCT. Inactivation of p53 is associated with the appearance of central consolidation within the pure GGO and may be useful as a molecular marker during the follow-up of a pure GGO.

EGFR and VEGF expression was immunohistochemically examined in a large cohort of cholangiocarcinoma. EGFR overexpression was an indepenent prognostic factor in intra-hepatic cholangiocarcinoma (IHCC) and associated with clinical features that may represent tumor progression and invasion in extra-hepatic cholangiocarcinoma (EHCC). VEGF expression was associated with intrahepatic metastasis in IHCC ⁽¹²⁸⁾. A mouse xenograft model of human cholangiocarcinoma cells (TKKK and OZ) has been established and the therapeutic effectiveness of an EGFR/VEGFR dual kinase inhibitor was evaluated. In vivo imaging analysis showed that tumor growth of both TKKK and OZ cells was significantly suppressed by this compound. Moreover, the chemopreventive effect of this kinase inhibitor was revealed by using a metastatic model of TKKK cells ⁽¹²⁸⁾. Collectively, these results indicate that molecular therapies targeting the EGFR/VEGFR pathways may offer a clinical benefit to cholangiocarcinoma patients.

BAC array-based CGH analyses of 135 primary gastric cancers identified many novel genomic loci with highly amplified DNA copies. By combining microarray-based gene expression analyses of the same tumor samples, many potential cancer-related genes whose overexpression was correlated with the copy number gain were identified. A chromosomal gain on 6p22-p21 has been observed in 8% of gastric cancers, and DNA copy number gains at the two loci of 6p21.2 and 6p21.1 were significantly correlated with a poor prognosis. Genomic amplification at 6p21 contains over fifty upregulated genes and downregulation of thirteen out of fifty genes by siRNA showed an inhibitory effect on cancer cell growth, suggesting that chromosome 6p21 harbors multiple cancer-related genes involved in the proliferation of gastric cancer cells.

A high-level chromosomal amplification of the 13q22 locus was identified by genome-wide screening for copy-number alterations in 50 primary poorly differentiated gastric cancers. By using siRNA-based assay, we identified a transcription factor as the candidate oncogene involved in not only cellular proliferation, but also in invasive activity. This gene is also highly expressed in primary shirrhous-type gastric cancers.

High-density array CGH analysis was applied to define genomic deletions in gastric cancer. More than 30 homozygously deleted loci were identified, including the previously known tumor suppressor genes (TSG). A novel putative TSG at 4q13, which functions as a RAS protein modulator, showed reduced expression in both primary tumors and cell lines. A frameshift mutation and promoter hypermethylation were observed in gastric cancer cell lines. Moreover, low expression of this TSG in tumors was associated with poor overall survival of patients. Thus, this TSG may contribute to gastric cancer progression.

The sub-chromosomal numerical aberrations of 44 primary pancreatic cancers were determined and chromosomal alterations that were significantly associated with a range of malignant phenotypes were identified. Expression profiling of amplified genes identified Smurf1 and TRRAP at 7q22.1, BCAS1 at 20q13.2-3, and VCL at 10q22.1 as potential novel oncogenes in pancreatic cancer ⁽¹²⁹⁾.

Genome-wide systematic profiling of somatic mutations by resequencing analysis will be beneficial for a comprehensive molecular understanding of carcinogenesis and identification of novel therapeutic targets. A resequencing analysis for kinase domains of the 90 TK genes (636 exons) in 29 primary pancreatic cancer specimens and 11 pancreatic cancer cell lines identified 15 nonsynonymous alterations. In particular, this analysis revealed the pathogenic mutation of NTRK3 in a KRAS/BRAF wild-type tumor, and two somatic mutations in the Src family kinases (YES1 and LYN) that are expected to cause structural changes.