H.J. Cho

Implications of time-series gene expression profiles of replicative senescence.

Although senescence has long been implicated in aging‐associated pathologies, it is not clearly understood how senescent cells are linked to these diseases. To address this knowledge gap, we profiled cellular senescence phenotypes and mRNA expression patterns during replicative senescence in human diploid fibroblasts. We identified a sequential order of gain‐of‐senescence phenotypes: low levels of reactive oxygen species, cell mass/size increases with delayed cell growth, high levels of reactive oxygen species with increases in senescence‐associated β‐galactosidase activity (SA‐β‐gal), and high levels of SA‐β‐gal activity. Gene expression profiling revealed four distinct modules in which genes were prominently expressed at certain stages of senescence, allowing us to divide the process into four stages: early, middle, advanced, and very advanced. Interestingly, the gene expression modules governing each stage supported the development of the associated senescence phenotypes. Senescence‐associated secretory phenotype–related genes also displayed a stage‐specific expression pattern with three unique features during senescence: differential expression of interleukin isoforms, differential expression of interleukins and their receptors, and differential expression of matrix metalloproteinases and their inhibitory proteins. We validated these phenomena at the protein level using human diploid fibroblasts and aging Sprague‐Dawley rat skin tissues. Finally, disease‐association analysis of the modular genes also revealed stage‐specific patterns. Taken together, our results reflect a detailed process of cellular senescence and provide diverse genome‐wide information of cellular backgrounds for senescence.

Profiling of Exome Mutations Associated with Progression of HBV-Related Hepatocellular Carcinoma

Recent advances in sequencing technology have allowed us to profile genome-wide mutations of various cancer types, revealing huge heterogeneity of cancer genome variations. However, its heterogeneous landscape of somatic mutations according to liver cancer progression is not fully understood. Here, we profiled the mutations and gene expressions of early and advanced hepatocellular carcinoma (HCC) related with Hepatitis B-viral infection. Integrative analysis was performed with whole-exome sequencing and gene expression profiles of the 12 cases of early and advanced HCCs and paired non-tumoral adjacent liver tissues. A total of 293 tumor-specific somatic variants and 202 non-tumoral variants were identified. The tumor-specific variants were found to be enriched at chromosome 1q particularly in the advanced HCC, compared to the non-tumoral variants. Functional enrichment analysis revealed frequent mutations at the genes encoding cytoskeleton organization, cell adhesion, and cell cycle-related genes. In addition, to elucidate actionable somatic mutations, we performed an integrative analysis of gene mutations and gene expression profiles together. This revealed the 48 mutated genes which were differentially mutated with concomitant gene expression enrichment. Of these, CTNNB1 was found to have a pivotal role in the differential progression of the HCC subgroup. In conclusion, our integrative analysis of whole-exome sequencing and transcriptome profiles could provide actionable mutations which might play pivotal roles in the heterogeneous progression of HCC.

P65 MUTATION SPECTRUM ASSOCIATED WITH THE PROGRESSION OF HBV-RELATED HEPATOCELLULAR CARCINOMA

P64 THE ULTRACONSERVED NON CODING RNA UC.158 IS DOWNSTREAM OF THE WNT/b-CATENIN PATHWAY IN LIVER CANCERS V. Paulus-Hock, A. Lampis, G. Ferrari, L. Boulton, R. Guest, D. Athineos, T. Jamieson, A. Veronese, R. Visone, R. Evans, G.J. Feng, T. Dale, M. Negrini, S. Forbes, T. Patel, O. Sansom, N. Valeri, C. Braconi. Institute of Cancer Sciences, University of Glasgow, Glasgow, Division of Molecular Pathology, Institute of Cancer Research, London, Scottish Centre for Regenerative Medicine, MRC Centre for Regenerative Medicine, Edinburgh, Beatson Institute for Cancer Research, Glasgow, United Kingdom; Aging Research Center, University of Chieti, Chieti, Italy; School of Biosciences, University of Cardiff, Cardiff, United Kingdom; University of Ferrara, Ferrara, Italy; Mayo Clinc, Jacksonville, FL, United States; Division of Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom E-mail: chiarabraconi@gmail.com