Hepatocellular carcinoma in Mongolia delineates unique molecular traits and a mutational signature associated with environmental agents

International audiencePurpose: Mongolia has the world’s highest incidence of hepatocellular carcinoma (HCC), with ~100 cases/105 inhabitants, although the reasons for this feature have not been thoroughly delineated. Experimental Design: We performed a molecular characterization of Mongolian (n=192) compared to Western HCCs (n=187) by RNA-seq and WES to unveil distinct genomic and transcriptomic features associated with environmental factors in this population. Results: Mongolian patients were younger, with higher female prevalence, and with predominantly HBV-HDV co-infection etiology. Mongolian HCCs presented significantly higher rates of protein-coding mutations (121 vs 70 mutations per tumor in Western), and in specific driver HCC genes (i.e. APOB, TSC2). Four mutational signatures characterized Mongolian samples, one of which was novel (SBS Mongolia) and present in 25% of Mongolian HCC cases. This signature showed a distinct substitution profile with a high proportion of T>G substitutions and was significantly associated with exposure to the environmental agent dimethyl sulfate (DMS, 71%), a 2A carcinogenic associated with coal combustion. Transcriptomic-based analysis delineated two molecular clusters, one with a highly inflamed profile, not present in Western HCC, and that were significantly associated with HBV-HDV etiology and female gender. Conclusions: Mongolian HCC has unique molecular traits with a high mutational burden and a novel mutational signature associated with genotoxic environmental factors present in this country