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 - 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 -