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.
Highlights
Hepatocellular carcinoma (HCC), the main form of primary liver cancer, is one of the leading causes of tumorrelated death worldwide [1]
This series was in keeping with the bimodal age structure described in Peruvian HCC patients, with 52.7% patients represented by adolescents and young adults (AYA) aged 44 or younger (n = 39) and 47.3% middle and old age individuals (MOA) above age 44 (n = 35) (Figure 1B and Table 1) [24]
The early-age onset HCC described in a significant fraction www.oncotarget.com www.oncotarget.com of Native American patients, originating from Alaskan and Andean regions, infected with the same endemic hepatitis B virus (HBV) subgenotype F1b, represents an illustration of this situation [10, 12]
Summary
Hepatocellular carcinoma (HCC), the main form of primary liver cancer, is one of the leading causes of tumorrelated death worldwide [1]. That is especially prevalent in the Andean Natives of Peru, in which non-cirrhotic, non-fibrolamellar HCCs develop in young patients with underlying infection by HBV subtype F1b [9, 10] In these tumors, the DNA repair machinery is constitutively activated in liver cancer cells, despite a low HBV replication level and a low-to-moderate mutation rate at major gene targets [10, 11]. A similar early-age onset of HCC, associated with the same clade of HBV, has been described in Alaskan Native people, 10,000 km distant from the Andean communities of Peru [12] This observation has raised the hypothesis of a particular dynamics in liver cancer shared by people with Indigenous American ancestries [8]. To the best of our knowledge, the present study represents the first integrative genomics characterization of a molecular subtype of cancer that preferentially affects people with Indigenous ancestry
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