TY - JOUR
T1 - Hepatocellular Carcinoma in Mongolia Delineates Unique Molecular Traits and a Mutational Signature Associated with Environmental Agents
AU - Torrens, Laura
AU - Puigvehí, Marc
AU - Torres-Martín, Miguel
AU - Wang, Huan
AU - Maeda, Miho
AU - Haber, Philipp K.
AU - Leonel, Thais
AU - García-López, Mireia
AU - Esteban-Fabró, Roger
AU - Leow, Wei Qiang
AU - Montironi, Carla
AU - Torrecilla, Sara
AU - Varadarajan, Ajay Ramakrishnan
AU - Taik, Patricia
AU - Campreciós, Genís
AU - Enkhbold, Chinbold
AU - Taivanbaatar, Erdenebileg
AU - Yerbolat, Amankyeldi
AU - Villanueva, Augusto
AU - Pérez-Del-Pulgar, Sofía
AU - Thung, Swan
AU - Chinburen, Jigjidsuren
AU - Letouzé, Eric
AU - Zucman-Rossi, Jessica
AU - Uzilov, Andrew
AU - Neely, Jaclyn
AU - Forns, Xavier
AU - Roayaie, Sasan
AU - Sia, Daniela
AU - Llovet, Josep M.
N1 - Funding Information:
This study was partially supported by Bristol-Myers Squibb. M. Puigvehí received a scholarship grant from Asociación Española para el Estudio del Hígado (AEEH). P.K. Haber is the recipient of a grant from the German Research Foundation (DFG, HA 8754/1-1). M. García-López 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-Fabró 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. Pérez-del-Pulgar is supported by the ISCIII through the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016 and 2017–2020 cofunded by the European Regional Development Fund (ERDF; PI16/00111 and PI19/00036). J. Zucman-Rossi’steamissupported by Inserm,Labex OncoImmunology Investissement d’Avenir and is “Equipe labelliséepar la Ligue Nationale Contre le Cancer.” X. Forns is supported by the ISCIII through the Plan Estatal de Investigación Científica y Técnica y de Innovación 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 Fundación Científica de laAsociacion Española ContraelCáncer andbytheGeneralitatdeCatalunya (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.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/10/15
Y1 - 2022/10/15
N2 - Purpose: Mongolia has the world's highest incidence of hepatocellular carcinoma (HCC), with ∼100 cases/100,000 inhabitants, although the reasons for this have not been thoroughly delineated. Experimental Design: We performed a molecular characterization of Mongolian (n = 192) compared with Western (n = 187) HCCs by RNA sequencing and whole-exome sequencing 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 coinfection 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 and 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 a signature of exposure to the environmental agent dimethyl sulfate (71%), a 2A carcinogenic associated with coal combustion. Transcriptomic-based analysis delineated three molecular clusters, two not present in Western HCC; one with a highly inflamed profile and the other significantly associated with younger female patients. 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.
AB - Purpose: Mongolia has the world's highest incidence of hepatocellular carcinoma (HCC), with ∼100 cases/100,000 inhabitants, although the reasons for this have not been thoroughly delineated. Experimental Design: We performed a molecular characterization of Mongolian (n = 192) compared with Western (n = 187) HCCs by RNA sequencing and whole-exome sequencing 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 coinfection 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 and 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 a signature of exposure to the environmental agent dimethyl sulfate (71%), a 2A carcinogenic associated with coal combustion. Transcriptomic-based analysis delineated three molecular clusters, two not present in Western HCC; one with a highly inflamed profile and the other significantly associated with younger female patients. 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.
UR - http://www.scopus.com/inward/record.url?scp=85140144666&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-22-0632
DO - 10.1158/1078-0432.CCR-22-0632
M3 - Article
C2 - 35998012
AN - SCOPUS:85140144666
SN - 1078-0432
VL - 28
SP - 4509
EP - 4520
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -