Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America

Abstract

We previously described a divergent clinical and molecular presentation of hepatocellular carcinoma (HCC) in Peru. The present study aimed to further characterize the tissue features associated with this singular nosological form of HCC in order to gain insight into the natural history of the disease. We performed an exploratory analysis of the histology of both tumor and non-tumor liver (NTL) tissues from 50 Peruvian HCC patients, and compared with that of 75 individuals with non-HCC liver tumor or benign liver lesions as a baseline for NTL features. We complemented this approach with a transcriptome analysis in a subset of NTL tissue samples and also performed an ultra-sensitive hepatitis B virus (HBV) detection in liver tissues of the patients. Overall, results highlighted the low rate of liver parenchymal alterations in a young patient cohort (median age: 40 years old), despite a strong prevalence of underlying HBV infection (c. 67%). Withal, liver clear cell foci of cellular alteration were genuinely associated with HCC and appended to some changes in immune and G protein-coupled receptor gene expression ontologies. Our findings confirm the occurrence of a particular setting of HCC in South America, a region where the pathophysiology of liver cancer remains largely unexplored.

Natural Occurrence of Mycotoxin-Producing Fusaria in Market-Bought Peruvian Cereals: A Food Safety Threat for Andean Populations

“…For example, the occurrence of early-age forms of liver cancer has been persistently described in patients from Peru, and more broadly, in South America [ 31 , 32 ]. This clinical presentation is associated with a peculiar mutation spectrum and the presence of hepatic foci of cellular alteration within the liver parenchyma that could be a hallmark of chronic liver insults caused by exposure to genotoxic substances, as observed in rodent animal models [ 33 , 34 , 35 , 36 ]. The potential brunt of dietary mycotoxin exposure has thus been suggested to intervene as a cofactor in this phenomenon [ 37 , 38 ].…”

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

“…Overall, Peruvian HCC did not conform with the molecular classes of HCC published previously. Moreover, Peruvian HCC displays relatively low rates of vascular invasion and recurrence despite a commonly heavy tumor burden (mean: 14 cm in diameter) [ 9 , 35 ]. These findings indicate that the form of HCC developed by Peruvians with Indigenous American ancestry represents a molecular subtype divergent from the unifying molecular classification of HCCs [ 3 , 4 ].…”

“…For example, a significant fraction of HCC cases in South America manifests with unusual early-age onset [ 7 , 8 ]. 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 ].…”

Metallomic Profile in Non-cirrhotic Hepatocellular Carcinoma Supports a Phenomenon of Metal Metabolism Adaptation in Tumor Cells

“…7,8 However, we observed within the non-tumor liver (NTL) parenchyma the presence of foci of cellular alteration in which cells are smaller compared to regular hepatocytes and exhibit an altered nuclear-cytoplasmic ratio. 7 These foci of cellular alteration showed also some degree of congruence with the co-expression of precancerous marker glutamine synthetase. Altogether, these ndings suggest that the clinical epidemiological situation encountered therein is due to some biological features intrinsic to the natural history of HCC in the population of Peru, and more broadly in South America.…”

“…6 Second, liver parenchyma exhibited a very low level of in ammatory response and an absence of brotic process, and this, despite a strong prevalence of underlying infection with hepatitis B virus. 7,8 However, we observed within the non-tumor liver (NTL) parenchyma the presence of foci of cellular alteration in which cells are smaller compared to regular hepatocytes and exhibit an altered nuclear-cytoplasmic ratio. 7 These foci of cellular alteration showed also some degree of congruence with the co-expression of precancerous marker glutamine synthetase.…”