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This study was partially supported by Bristol-Myers Squibb. M. Puigveh? received a scholarship grant from Asociacion Espanola para el Estudio del Higado (AEEH) . P.K. Haber is the recipient of a grant from the German Research Foundation (DFG, HA 8754/1-1) . M. Garc?a-Lo?pez is supported by the i-PFIS program (fellowship IFI18/00006) of the Instituto de Salud Carlos III (ISCIII) , cofunded by the European Social Fund. R. Esteban-Fabro? is supported by a doctoral training grant (BES-2017-081286) from MCIN/AEI/10.13039/501100011033 and the European Social Fund (ESF) . A.R. Varadarajan is supported by the US Department of Defense grant (CA150272P3) and the Tisch Cancer Institute (Cancer Center grant P30 CA196521) . S. Pe?rez-del-Pulgar is supported by the ISCIII through the Plan Estatal de Investigacio?n Cient?fica y Te?cnica y de Innovacio?n 2013-2016 and 2017-2020 cofunded by the European Regional Devel-opment Fund (ERDF; PI16/00111 and PI19/00036) . J. Zucman-Rossi?s team is supported by Inserm, Labex OncoImmunology Investissement d'Avenir and is Equipe labellisee par la Ligue Nationale Contre le Cancer.X. Forns is supported by the ISCIII through the Plan Estatal de Investigacio?n Cient?fica y Te?cnica y de Innovacio?n 2013-2016 and 2017-2020 cofunded by the ERDF (PI18/00079) , by the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (grant 2017_SGR_1753) , and by CERCA Programme/Generalitat de Catalunya. D. Sia is supported by the Gilead Sciences Research Scholar Program in Liver Disease. J.M. Llovet is supported by grants from the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (MICINN, PID2019-105378RB-I00) , NIH (R01 DK128289-01) , HUNTER (Ref. C9380/A26813) through a partnership between Cancer Research UK, Fondazione AIRC and Fundacion Cientifica de la Asociacion Espanola Contra el Cancer and by the Generalitat de Catalunya (AGAUR, SGR-1358) . We thank Clara Rossi, a Fellow at Mount Sinai, and Luca Niebla, an MD student at the University of Barcelona, for their help.

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

Publicat a:Clinical Cancer Research. 28 (20): 4509-4520 - 2022-10-15 28(20), DOI: 10.1158/1078-0432.ccr-22-0632

Autors: Torrens, L; Puigvehí, M; Torres-Martín, M; Wang, H; Maeda, M; Haber, PK; Leonel, T; García-López, M; Esteban-Fabró, R; Leow, WQ; Montironi, C; Torrecilla, S; Varadarajan, AR; Taik, P; Campreciós, G; Enkhbold, C; Taivanbaatar, E; Yerbolat, A; Villanueva, A; Pérez-del-Pulgar, S; Thung, S; Chinburen, J; Letouzé, E; Zucman-Rossi, J; Uzilov, A; Neely, J; Forns, X; Roayaie, S; Sia, D; Llovet, JM

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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.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.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.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.

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