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

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.

A preoperative nomogram for predicting long-term survival after resection of large hepatocellular carcinoma (>10 cm)

“…The identification of molecular signatures should eventually help to better sub-stratify these patients with no preoperative predictor and optimize medical intervention. 48,49 In conclusion, we believe that this new nomogram could represent a valuable tool to help decision-making of LR intervention or abstention in the management of HCC larger than 10 cm in diameter.…”

Epidemiology and aetiology of hepatocellular carcinoma in Sub-Saharan Africa

“…Proliferative HCC, characterised by high serum AFP levels, leads to more aggressive tumours and poor prognosis and is associated with HBV infection [62,65,67] . This unifying molecular classification aims to lead to stratified therapy strategies [68] . However, this classification has been based on studies carried out on HCC patients from Asia, Europe and North America, in which African and indigenous populations have been under-represented.…”

Metallomic profile in non-cirrhotic hepatocellular carcinoma supports a phenomenon of metal metabolism adaptation in tumor cells

“…First, Peruvian HCC displayed a unique mutation spectrum, in which the major class of alterations was epitomized by genetic short indels 6 . Second, the integrative analysis revealed that Peruvian tumors correspond to a divergent molecular subtype of HCC with unique gene expression signature and global DNA hypermethylation pattern, albeit genome-wide hypomethylation was hitherto viewed as a hallmark of HCC 7 . Third, liver parenchyma exhibited a very low level of inflammatory response and an absence of fibrotic process, and that, despite a strong prevalence of underlying infection with hepatitis B virus 8 , 9 .…”