Our recent progress includes: (1)Human hepatocarcinogenes is as a multi-step process starting from dysplastic lesions to early carcinoma (eHCC) that ultimately progresses to HCC (pHCC). The probability of malignant transformation of the pre-neoplastic lesions, which often co-exist with eHCC and pHCC in an individual patient, is not defined. Therefore, definition of the sequential molecular events leading to HCC is urgently needed and represents a major challenge in the clinical management of patients at risk. This study is the first to apply integrative 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. We report that the transcriptomes of early lesions including eHCC were surprisingly homogenous despite a progressive increase in immune response and proliferation. Activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and was centered on TGFbeta, WNT, NOTCH and EMTrelated genes reflecting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant which is preferentially down-regulated in pHCC. Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC.
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