Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry

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Bertani, Stéphane
Cano, Luis
Casavilca-Zambrano, Sandro
Cerapio, Juan Pablo
Dejean, Anne
Fournié, Jean-Jacques
López, Ignacio
Marchio, Agnès
Pineau, Pascal
Régnault, Béatrice
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Hepatocellular carcinoma (HCC) usually afflicts individuals in their maturity after a protracted liver disease. Contrasting with this pattern, the age structure of HCC in Andean people displays a bimodal distribution with half of the patients developing HCC in adolescence and early adulthood. To deepen our understanding of the molecular determinants of the disease in this population, we conducted an integrative analysis of gene expression and DNA methylation in HCC developed by 74 Peruvian patients, including 39 adolescents and young adults. While genome-wide hypomethylation is considered as a paradigm in human HCCs, our analysis revealed that Peruvian tumors are associated with a global DNA hypermethylation. Moreover, pathway enrichment analysis of transcriptome data characterized an original combination of signatures. Peruvian HCC forgoes canonical activations of IGF2, Notch, Ras/MAPK, and TGF-β signals to depend instead on Hippo/YAP1, MYC, and Wnt/β-catenin pathways. These signatures delineate a homogeneous subtype of liver tumors at the interface of the proliferative and non-proliferative classes of HCCs. Remarkably, the development of this HCC subtype occurs in patients with one of the four Native American mitochondrial haplogroups A-D. Finally, integrative characterization revealed that Peruvian HCC is apparently controlled by the PRC2 complex that mediates cell reprogramming with massive DNA methylation modulating gene expression and pinpointed retinoid signaling as a potential target for epigenetic therapy. © 2021 Cerapio et al.
This work was supported by the Alliance pour les Sciences de la Vie et de la Santé (AVIESAN), ITMO Cancer ENV201408 (to S.B.) and the Ligue Contre le Cancer (to P.P.). J.P.C. was a recipient of a doctoral scholarship from the Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica (FONDECYT) 212-2015-FONDECYT and was supported by a fellowship from Campus France 941211E; L.C. was supported by a doctoral fellowship from IRD ARTS-2016-878573B; I.L. was supported by a postdoctoral fellowship from the Fondation ARC pour la Recherche sur le Cancer PDF20170505624; J.J.F. has received funding from the Agence Nationale de la Recherche (ANR) under the Investments for the Future program 11-LABX-0068; S.C.Z. and E.R. have received funding from the World Bank Group and FONDECYT-CONCYTEC under the Research Infrastructure Improvement program 016-2018-FONDECYT/BM; and S.B. has received funding from the European Union’s Horizon 2020 Framework program under the Marie Skłodowska-Curie Actions 823935.
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Liver cancer, Hepatitis B virus, Indigenous people, Integrative genomics