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

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Cited 9 times in Web of Science logo

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Grant support

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.

Analysis of institutional authors

Torres De Dalmases, Maria Del CarmenAuthorTorrens LAuthorTorres-Martín MAuthorLeonel TAuthorGarcía-López MAuthorEsteban-Fabró RAuthorMontironi CAuthorTorrecilla SAuthorCamprecios GAuthorVillanueva AAuthorPerez-Del-Pulgar SAuthorForns XAuthorLlovet JmCorresponding Author

August 24, 2022

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Article

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

Authors: 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

Affiliations

Bristol Myers Squibb, Princeton, NJ USA - Author

Hospital Clinic of Barcelona, Barcelona, spain, Spain. - Author

Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA - Author

Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Liver Canc Program,Div Liver Dis, New York, NY 10029 USA - Author

Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA - Author

Icahn School of Medicine at Mount Sinai, New York, New York, United States. - Author

IDIBAPS, Barcelona, Spain. - Author

IMIM Hosp del Mar Med Res Inst, Parc Salut Mar, Hepatol Sect, Dept Gastroenterol, Barcelona, Spain - Author

INSERM, Paris, France. - Author

Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Catalonia, Spain - Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain. - Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona, Barcelona, Barcelona, Spain. - Author

Natl Canc Ctr, Hepatopancreat Biliary Surg Dept, Ulan Bator, Mongolia - Author

Natl Canc Ctr, Ulaanbaatar, Mongolia - Author

Sema4, Stamford, CT USA - Author

Singapore Gen Hosp, Dept Anat Pathol, Singapore, Singapore - Author

Univ Barcelona, CIBEREHD, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Liver Unit,Hosp Clin, Barcelona, Spain - Author

Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Translat Res Hepat Oncol,Liver Unit, Barcelona, Spain - Author

Univ Paris 13, Univ Paris, Sorbonne Univ, Ctr Rech Cordeliers,Inserm,Funct Genom Solid Tumo, Paris, France - Author

White Plains Hosp, Dept Surg, White Plains, NY USA - Author

Abstract

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.

Keywords

cancergenotypeshigh prevalencelandscapeprecorernatriple infectionAdultAgedAmino acid substitutionApob geneApolipoprotein bApolipoproteins bArticleCancer riskCarcinoma, hepatocellularClinical featureCoalCohort analysisCombustionControlled studyDimethyl sulfateEnvironmental factorEpidemiologyFemaleGene clusterGene mutationGenetic associationGenetic traitGeneticsGenotoxicityHepatitis bHepatitis dHepatitis-delta virusHumanHuman tissueHumansLiver cell carcinomaLiver neoplasmsLiver tumorMajor clinical studyMaleMongoliaMongolian (people)MutationMutational analysisRna sequencingTranscriptomeTsc2 geneTumor mutational burdenTumor-related geneWhole exome sequencing

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Clinical Cancer Research due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 22/241, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 5.85, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-05, the following number of citations:

WoS: 9
Scopus: 6
Europe PMC: 8

Impact and social visibility

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France; Jersey; Mongolia; Singapore; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Torrens Fontanals, Laura) and Last Author (Llovet Bayer, Josep M.).