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Invited talk 3
Prof. Nathalie Wong

Department of Surgery,

Chinese University of Hong Kong

Prof. Nathalie Wong obtained her D.Phil. in Clinical Biochemistry from University of Oxford, UK, and post-doctoral training at King’s College School of Medicine and Dentistry, University of London, UK. She is now Professor and Research Director at the Dept of Surgery, Chinese University of Hong Kong. Prof. Wong’s research focuses on the genomics of human hepatocellular carcinoma (HCC) and mechanism underscoring liver carcinogenesis.  Her group has previously defined vital molecular events and clonal heterogeneities in HCC. Prof. Wong’s current research includes 3rd generation long-read transcriptome sequencings of HCC to define tumor-related splicing variants, functional characterization of somatic alterations for cancer-causing effects and tumor intrinsic genetic events in mediating immune escape of HCC.

Topic:  Molecular Distinctions of NAFLD-associated Liver Cancer accentuate on

β-Catenin-mediated Immune Evasion

Summary:  Metabolic syndrome can lead to the clinical manifestation of non-alcoholic fatty liver disease (NAFLD) and eventually to hepatocellular carcinoma (HCC) as part of the natural history of NAFLD. Despite a strong causative link, NAFLD-HCC is often underrepresented in systematic genome explorations. Here, we sequenced tumor-normal pairs from patients diagnosed with NAFLD-HCC. Mutational process operative in NAFLD-liver inferred susceptibility to tumor formation through defective DNA mismatch-repair pathway. Dense promoter mutations accentuated activated transcriptional regulators in NAFLD-HCC, in particular the enrichment of myc-associated zinc-finger protein (MAZ) activities. Somatic events common in HCCs arising from NAFLD and viral hepatitis B infection underscore similar driver pathways, although an incidence shift highlights CTNNB1mut dominance in NAFLD-HCC (33%). Immune exclusion correlated evidently with CTNNB1mut. ChIP-seq integrated with transcriptome and immune profiling showed a novel transcriptional axis of CTNNB1mut/TNFRSF19/repressed chemokines (including IL6 and CXCL8). This phenomenon could be reverted by Wnt-modulator ICG001. In sum, the increasing prevalence of metabolic syndrome in adult populations poised NAFLD-induced HCC to be the major type of liver cancer of the 21st century. We showed a strong “field effect” in NAFLD-liver from mutational signatures detected and a mechanistic path for activated b-catenin in reshaping the tumor-immune microenvironment in favor of immune exclusion via TNFRSF19 inhibition of chemokine secretions.

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