Our recent progress includes:(1)Mutations in TP53, a tumor suppressor gene, are associated with prognosis of many cancers. However, the prognostic values of TP53 mutation sites are not known for patients with hepatocellular carcinoma (HCC) because of heterogeneity in their geographic and etiologic backgrounds.TP53 mutations were investigated in a total of 409 HCC patients, including Chinese (n = 336) and white (n = 73) patients, using the direct sequencing method. A total of 125 TP53 mutations were found in Chinese patients with HCC (37.2%). HCC patients with TP53 mutations had a shorter overall survival time compared with patients with wild-type TP53 (hazard ratio [HR], 1.86;95% confidence interval [CI]: 1.37-2.52;P <.001). The hot spot mutations R249S and V157F were significantly associated with worse prognosis in univariate (HR, 2.11;95% CI: 1.51-2.94;P <.001) and multivariate analyses (HR, 1.79;95% CI: 1.29-2.51;P <.001). Gene expression analysis revealed the existence of stem cell-like traits in tumors with TP53 mutations. These findings were validated in breast and lung tumor samples with TP53 mutations.TP53 mutations, particularly the hot spot mutations R249S and V157F, are associated with poor prognosis for patients with HCC. The acquisition of stem cell-like gene expression traits might contribute to the aggressive behavior of tumors with TP53 mutation.(2)Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome.(3)Cholangiocarcinoma (CCA) is a heterogeneous disease with dismal outcome accounting for 5% to 10% of primary liver cancers. We developed a genomic and genetic characterization of CCA to classify patients according to clinical outcome and to discover novel therapeutic modalities. We profiled the transcriptome from 104 surgically resected CCAs from Australia, Europe and USA and epithelial and stromal compartments microdissected from 23 tumors. Mutational analysis of KRAS, EGFR and BRAF was performed on 69 tumors, and DNA copy number variation on 48 tumors. Targets were validated by Western blotting and immunohistochemistry, and by integrating seven human CCA cell lines with the patient cohort followed by treatment with trastuzumab and lapatinib. Patients were classified into two distinct groups as defined by overall survival (P <.0007), early recurrence (P <.001) and KRAS mutations (24.6%). Class comparison identified four survival subgroups (SGI-IV, P <.03) with SGIII characterized by genes associated with proteasome activity and worst clinical prognosis. Tumor epithelium was defined by deregulation of HER2-network and frequent overexpression of EGFR, MET, pRPS6 and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, a HER2 and EGFR inhibitor, was more effective in reducing viability of CCA cell lines than trastuzumab. Our study provides new insights into the molecular pathogenesis of CCA and identifies a previously unrecognized subgroup of patients characterized by KRAS mutations and increased EGFR and HER2 signaling who may benefit from dual-target tyrosine kinase inhibitors. Transcriptional enrichment of genes driving proteasome activity in a subgroup of patients with worst prognosis presents new therapeutic options.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Staib, Frank; Krupp, Markus; Maass, Thorsten et al. (2014) CellMinerHCC: a microarray-based expression database for hepatocellular carcinoma cell lines. Liver Int 34:621-31
Marquardt, Jens U; Thorgeirsson, Snorri S (2014) SnapShot: Hepatocellular carcinoma. Cancer Cell 25:550.e1
Marquardt, Jens U; Thorgeirsson, Snorri S (2014) Next-generation genomic profiling of hepatocellular adenomas: a new era of individualized patient care. Cancer Cell 25:409-11
Andersen, Jesper B; Thorgeirsson, Snorri S (2014) A perspective on molecular therapy in cholangiocarcinoma: present status and future directions. Hepat Oncol 1:143-157
Marquardt, Jens U; Seo, Daekwan; Andersen, Jesper B et al. (2014) Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits. J Hepatol 60:346-353
Matter, Matthias S; Decaens, Thomas; Andersen, Jesper B et al. (2014) Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J Hepatol 60:855-65
Jia, Jinping; Parikh, Hemang; Xiao, Wenming et al. (2013) An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer. BMC Med Genomics 6:33
Marquardt, Jens U; Fischer, Kerstin; Baus, Katharina et al. (2013) Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients. Hepatology 58:1054-64
Marquardt, Jens U; Thorgeirsson, Snorri S (2013) Sall4 in ""stemness""-driven hepatocarcinogenesis. N Engl J Med 368:2316-8
Kwon, So Mee; Kim, Dong-Sik; Won, Nam Hee et al. (2013) Genomic copy number alterations with transcriptional deregulation at 6p identify an aggressive HCC phenotype. Carcinogenesis 34:1543-50

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