Oncotarget 475 www.oncotarget.com www.oncotarget.com Oncotarget, 2021, Vol. 12, (No. 5), pp: 475-492 Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry Juan Pablo Cerapio 1,4 , Agnès Marchio 2 , Luis Cano 3 , Ignacio López 2 , Jean-Jacques Fournié 4 , Béatrice Régnault 5 , Sandro Casavilca-Zambrano 6 , Eloy Ruiz 7 , Anne Dejean 2 , Stéphane Bertani 8,* and Pascal Pineau 2,* 1 Sorbonne Université, Institut Pasteur, Unité Organisation Nucléaire et Oncogenèse, INSERM, U 993, Paris, France 2 Institut Pasteur, Unité Organisation Nucléaire et Oncogenèse, INSERM, U 993, Paris, France 3 Université de Rennes 1, INSERM, CNRS, U 1241 NUMECAN, Rennes, France 4 Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, INSERM, UPS, UMR 1037, CNRS, ERL 5294, Toulouse, France 5 Institut Pasteur, Centre d'Innovation et Recherche Technologique, Plateforme de Génotypage des Eucaryotes, Paris, France 6 Instituto Nacional de Enfermedades Neoplásicas, Departamento de Patología, Banco de Tejidos Tumorales, Lima, Peru 7 Instituto Nacional de Enfermedades Neoplásicas, Departamento de Cirugía en Abdomen, Lima, Peru 8 Université de Toulouse, IRD, UPS, UMR 152 PHARMADEV, Toulouse, France * These authors contributed equally to this work Correspondence to: Pascal Pineau, email: pascal.pineau@pasteur.fr Stéphane Bertani, email: stephane.bertani@ird.fr Keywords: hepatitis B virus; indigenous people; integrative genomics; liver cancer Received: September 24, 2020 Accepted: January 26, 2021 Published: March 02, 2021 Copyright: © 2021 Cerapio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT 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. Research Paper