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Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits.
- Source :
-
Journal of hepatology [J Hepatol] 2014 Feb; Vol. 60 (2), pp. 346-353. Date of Electronic Publication: 2013 Oct 26. - Publication Year :
- 2014
-
Abstract
- Background & Aims: Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk.<br />Methods: We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, eHCC (n = 5) and pHCC (n = 3) from 8 HCC patients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were performed to characterize the genomic alterations during hepatocarcinogenesis.<br />Results: We report that changes in transcriptomes of early lesions including eHCC were modest and surprisingly homogenous. Extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and were centered on TGFβ, WNT, NOTCH, and EMT-related genes highlighting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant preferentially down-regulated in pHCC.<br />Conclusions: Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC, and merit larger prospective investigations to develop a modified clinical-decision making algorithm based on the individualized next-generation sequencing analyses.
- Subjects :
- Adult
Aged
Carcinogenesis genetics
Carcinoma, Hepatocellular etiology
Carcinoma, Hepatocellular pathology
Cell Transformation, Neoplastic genetics
Disease Progression
Female
Gene Expression Profiling
Humans
Liver Neoplasms etiology
Liver Neoplasms pathology
Male
Middle Aged
Mutation
Polymorphism, Single Nucleotide
RNA, Neoplasm genetics
Tumor Microenvironment genetics
Carcinoma, Hepatocellular genetics
Liver Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0641
- Volume :
- 60
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 24512821
- Full Text :
- https://doi.org/10.1016/j.jhep.2013.10.014