Hepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. Previous work showed that in the western part of North Africa, a region of low incidence of HCC, mutations are scarce for this tumor type. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, thus, to characterize DNA methylation in HCC from North-African patients. A set of 11 loci was investigated in a series of 45 tumor specimens using methylation-specific and combined-bisulfite restriction assay PCR. Results obtained on clinical samples were subsequently validated in liver cancer cell lines. DNA methylation at tumor suppressor loci is significantly higher in samples displaying chromosome instability. More importantly, DNA methylation was significantly higher in Arg/Arg when compared to Pro/Pro genotype carriers at codon 72 rs1042522 of TP53 (65% vs 20% methylated loci, p = 0.0006), a polymorphism already known to affect somatic mutation rate in human carcinomas. In vitro experiments in cell lines indicated that enzymes controlling DNA methylation were differentially regulated by codon 72 Arg or Pro isoforms of p53. Furthermore, the Arg72-carrying version of p53 was shown to re-methylate DNA more rapidly than the pro-harboring isoform. Finally, Pro-carrying cell lines were shown to be significantly more resistant to decitabine treatment (two-fold, p = 0.005). Our data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC. It suggests, in addition, that rs1042522 genotype may predict sensitivity to epigenetic-targeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, therefore, apply essentially to population living in similar areas. Surveys on populations submitted to highly mutagenic conditions as perinatally-acquired chronic hepatitis B or aflatoxin B1 exposure remained to be conducted to validate our observations as a general model.

RT-qPCR detection of SARS-CoV-2 RNA still represents the method of reference to diagnose and monitor COVID-19. From the onset of the pandemic, however, doubts have been expressed concerning the sensitivity of this molecular diagnosis method. Droplet digital PCR (ddPCR) is a third-generation PCR technique that is particularly adapted to detecting low-abundance targets. We developed two-color ddPCR assays for the detection of four different regions of SARS-CoV-2 RNA, including non-structural (IP4-RdRP, helicase) and structural (E, N) protein-encoding sequences. We observed that N or E subgenomic RNAs are generally more abundant than IP4 and helicase RNA sequences in cells infected in vitro, suggesting that detection of the N gene, coding for the most abundant subgenomic RNA of SARS-CoV-2, increases the sensitivity of detection during the highly replicative phase of infection. We investigated 208 nasopharyngeal swabs sampled in March-April 2020 in different hospitals of Greater Paris. We found that 8.6% of informative samples (n = 16/185, P < 0.0001) initially scored as “non-positive” (undetermined or negative) by RT-qPCR were positive for SARS-CoV-2 RNA by ddPCR. Our work confirms that the use of ddPCR modestly, but significantly, increases the proportion of upper airway samples testing positive in the framework of first-line diagnosis of a French population.

Despite decades of concern over the carcinogenic potential of agricultural pesticides, toxicological studies relying on single endpoints have yet to establish a definitive link between environmental pesticide exposure and cancer in real-world contexts. Here we use an integrative spatial Bayesian framework that merges high-resolution environmental pesticide risk modelling with comprehensive cancer registry data to map pesticide-linked cancer clusters in Peru with unprecedented precision. Our process-based model, encompassing 31 key pesticide active ingredients, together with an innovative stratification of cancer cases by developmental lineage, reveals a robust spatial association between environmental pesticide exposure risk and cancer incidence. In pesticide-associated cancer hotspots, exposomic profiling of liver tissue—a primary target of chemical carcinogens—uncovers a distinct transcriptomic signature of pesticide exposure, implicating a non-genotoxic mode of action that disrupts core regulatory circuitries sustaining cell identity. Collectively, these findings strongly support a mechanistic link between pesticide exposure and cancer, challenging assumptions of human non-carcinogenicity derived from reductionist experimental models. This study redefines the exposome as a lineage-conditioned, mechanistically tractable framework and shows how complex pesticide mixtures can contribute to carcinogenic trajectories, with profound and far-reaching implications for global health policy and socio-ecological equity.

Intrahepatic cholangiocarcinoma (ICA) is a highly aggressive primary liver cancer, which originates from the epithelial cells of the bile ducts. The transcriptional profile of metabolic enzymes was investigated at both bulk and single-cell levels in tumor samples from distinct ICA cohorts. In a training cohort (TCGA consortium), 16 genes encoding for metabolic enzymes were found overexpressed in cases with poor survival. A computed metabolic gene expression score was significantly associated with worse ICA prognosis at the univariate level (overall survival [OS] log-rank p = 8.2e-4). After adjusting for Ishak fibrosis score and tumor staging, the metabolic expression remained an independent predictor of poor prognosis (multivariate OS log-rank p = 0.01). Seven genes encoding key enzymes (FH, MAT2B, PLOD2, PLOD1, PDE6D, ALDOC, and NT5DC3) were validated as markers of the proliferative subclass of ICA in the GSE32225 dataset, related to poor prognosis. The metabolic score was significantly different between the inflammatory and proliferative subclasses in the validation cohort (p < 2.2e-16). At the single-cell level, in the tumor microenvironment of 10 ICA patients, these seven enzymes were predominantly expressed by malignant cells. The single-cell metabolic score was thus higher in malignant cells. This study identifies a metabolic transcriptional program linked to poor prognosis in ICA, independent of fibrosis and tumor staging.

Background: Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. Methods: Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. Results: Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. Conclusions: The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments.