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RNA-seq of Liver Cancer

ABSTRACT: The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome (WGS) and whole exome sequencing (WGS), integrated with DNA methylation and RNA sequencing (RNA-seq) data. The present series corresponds to 161 RNA-seq samples from tumors with matched WES or WGS. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

PROVIDER: EGAS00001002879 | EGA |

REPOSITORIES: EGA

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Project description:A complete understanding of molecular mechanisms that underlie cancer onset and progression could provide a basis to improve early diagnosis and more effective treatment. However, this is still a challenge in human, partly due to the difficulty of analyzing the early stages of the disease. In this context, genetically engineered mice represent a valuable alternative to model human carcinogenesis. Here, we studied cancer development in c-Myc/Tgfa transgenic mice that developed liver tumors which closely reproduce a subset of human hepatocellular carcinoma (HCC) with a poor prognosis. By using a functional genomics approach from early to late stages of HCC development, we demonstrated that hepatocarcinogenesis in c-Myc/Tgfa mice resulted from a progressive accumulation of transcriptional alterations due to an active hepatocyte proliferation in a chronic oxidative stress environment generated by a general metabolic disorder. One striking observation was the deregulation of numerous immune-related genes starting from an early stage of the disease. Particularly, we showed that activating ligands for natural killer (NK) cells were specifically induced in dysplastic hepatocytes which simultaneously lost the expression of MHC-I molecules. Besides this early mechanism of NK-mediated immune surveillance, we further reported a drastic decrease in hepatic NK cell population which may indeed contribute to the emergence and clonal expansion of progenitors for liver tumors. In conclusion, our study provided a detailed and comprehensive characterization of hepatocarcinogenesis in c-Myc/Tgfa transgenic mice and emphasized the critical role of the innate immune surveillance disruption at the early stages of liver cancer. In the present study, we reported a detailed and comprehensive dynamic characterization of the cellular and molecular alterations involved in tumor onset and progression in the liver of c-Myc/Tgfa double-transgenic mice (B6CBAxCD1 background). Liver samples from male animals were collected at various time-points ranging from 3 weeks to 9 months for c-Myc/Tgfa double-transgenic mice, or 18 months for c-Myc and Tgfa single-transgenic mice. Tissue samples were divided into two parts; one was fixed in 10% formalin for histological evaluation and the other was used for RNA analysis. Total RNAs were isolated from livers with moderate or severe hepatocyte dysplasia (at 3 weeks and 3 months, respectively), as well as from HCC and surrounding non-tumor livers (5-15 mice per group). Total RNAs were also isolated from the livers of B6CBAxCD1 wild-type mice at 3 weeks and 3 months. RNAs isolated from the normal livers of B6CBA WT mice (3 months old, n=10) were pooled and used as a common technical reference for all microarray experiments.

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RNA-seq of Liver Cancer

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