title: Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  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.
  
  
  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.
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.|Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.
authors: Jens U
authors: JU
authors: Marquardt
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.
authors: Daekwan
authors: D
authors: Seo
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.
authors: Jesper B
authors: JB
authors: Andersen
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.
authors: Matthew C
authors: MC
authors: Gillen
authors: Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.
authors: Myoung Soo
authors: MS
authors: Kim
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.
authors: Elizabeth A
authors: EA
authors: Conner
authors: Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.
authors: Peter R
authors: PR
authors: Galle
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.
authors: Valentina M
authors: VM
authors: Factor
authors: Department of Pathology, Brain Korea 21 Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University, Seoul, Korea.
authors: Young Nyun
authors: YN
authors: Park
authors: Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH.
authors: Snorri S
authors: SS
authors: Thorgeirsson
mesh_terms: D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012334:RNA, Neoplasm / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D012334:RNA, Neoplasm