👤 Koji Arihiro

Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome. Show less

Both cyclin D1 and c-myc are key molecules in breast cancer carcinogenesis, and their transcriptional level and stability are regulated through several signaling pathways, including the Wnt signaling pathway. We performed immunohistochemical and mutational analyses of Wnt signaling components to investigate the association of Wnt signaling alterations with breast cancer carcinogenesis using 49 surgically resected primary breast cancer samples. Positive staining of cyclin D1 and c-myc was observed in 55.1% and 30.6% of the 49 breast cancer samples, respectively. Aberrant cytoplasmic expression of beta-catenin, which indicates the existence of alterations in the Wnt signaling pathway, was observed in 38.8% of breast cancer samples, though no mutation was found in the beta-catenin and Axin 1 genes. Reduced expression of APC was observed in 34.7% of samples. Statistical analysis revealed strong correlations between overexpression of beta-catenin and that of cyclin D1 and c-myc (p=0.0001 and 0.0117, respectively). Furthermore, overexpression of beta-catenin was significantly correlated with reduced expression of APC (p=0.0127). Wnt signaling alterations were frequently observed in breast cancer from the results of beta-catenin immunohistochemistry, although no mutation in the components of the Wnt signaling pathway was found in the present study. Based on the statistical analyses, we speculated that reduced expression of APC leads to overexpression of beta-catenin, and aberrant expression of cyclin D1 and c-myc mainly depends on alterations in the Wnt signaling pathway in breast cancer. Show less

The mechanisms of carcinogenesis in intrahepatic cholangiocarcinoma (ICC) are not well characterized although alterations in several oncogenes and onco-suppressor genes have been reported to occur in ICC. In the present study, we focused on alterations in the Wnt signaling components and target genes by analyzing 24 surgically resected samples of ICC. Immunohistochemical analysis of beta-catenin showed positive staining in cytoplasm and/or nucleus in 58.3% of the samples, indicating the presence of alterations in the Wnt signaling pathway in these samples. In sequencing analyses, mutations in the beta-catenin, adenomatous polyposis coli and Axin 1 genes were observed in 8.3, 12.5 and 41.7%, respectively, of the 24 ICC samples; however, the functional significance of these mutated genes is controversial. Furthermore, cyclin D1, c-myc and urinary-type plasminogen activator receptor, which are the downstream target genes in the Wnt signaling pathway, were overexpressed in 41.7, 41.7 and 58.3%, respectively, of the 24 ICC samples. The overexpression of cyclin D1 was statistically correlated with that of beta-catenin. Based on these results, we speculated that the Wnt signaling pathway plays an important role in carcinogenesis in ICC through overexpression of its target genes, particularly cyclin D1. Show less