Introduction: Hepatocellular carcinoma (HCC) is the third most frequent cancer of digestive tract tumors in Peru, with a high mortality rate of 17.7 per 100,000 inhabitants. A significant number of HCC cases in Peru do not follow the classic clinical epidemiology of the disease described in other parts of the world. Those patients present with a distinct transcriptome profile and a singular tumor process, suggesting a particular type of hepatocarcinogenesis in a portion of the Peruvian population. Aim: Our aim was to understand the clinical and biologic involvement of the epigenetic profile (methylation) and gene expression (transcriptome) of HCC in Peruvian patients. Methods: HCC and liver transcriptome and DNA methylation profiles were evaluated in 74 Peruvian patients. Results: When grouped by age, there was greater DNA methylation in younger patients with HCC but no differences with ...

In Peru, hepatocellular carcinoma (HCC) arises in young non-cirrhotic patients. Hepatitis B virus (HBV) is suspected to be the prominent etiological agent. We thus performed a comprehensive molecular study of HBV infection in 65 Peruvian HCC patients. Only 51% were considered as persistently infected at the onset. HBV DNA was found by PCR in the tumor and/or matched non-tumor liver tissues in more than 80% of cases (n = 53/65). HBV DNA was significantly more abundant in livers of younger patients than in those of the older ones. We consistently observed low viral DNA burden (0.1-6.5 copies for 100 cells), with viral genomes in younger patients displaying higher proportion of mutations at di-pyrimidines (TpT and CpC, P = 0.006). A drastic activation of multiple DNA repair pathways in tumors of younger patients was observed. Our observations clearly challenge the current vision that associ...

In the developing world, most patients with hepatocellular carcinoma present with advanced-stage disease, considered to be incurable based on current therapeutic algorithms. Here, we demonstrate that curative liver resection is achievable in a portion of Peruvian patients not addressed by these treatment algorithms. We conducted a retrospective cohort study of 253 hepatocellular carcinoma patients that underwent a curative hepatectomy between 1991 and 2011 at the National Cancer Institute of Peru. The median age of the cohort was 36 years, and merely 15.4% of the patients displayed cirrhosis. The average tumor size was over 14 cm in diameter, resulting in 76.3% of major hepatectomies performed. The 5- and 10-year survival probability estimates were 37.5% and 26.2%, respectively. Age (>44 vs. ≤44 years old; P = 0.005), tumor size (>10 cm vs. ≤10 cm in diameter; P = 0.009), cirrh...

Background: It has previously been demonstrated that a fraction of patients with hepatocellular carcinoma (HCC) > 10 cm can benefit from liver resection. However, there is still a lack of effective decision-making tools to inform intervention in these patients. Methods: We analysed a comprehensive set of clinical data from 234 patients who underwent liver resection for HCC >10 cm at the National Cancer Institute of Peru between 1990 and 2015, monitored their survival, and constructed a nomogram to predict the surgical outcome based on preoperative variables. Results: We identified cirrhosis, multifocality, macroscopic vascular invasion, and spontaneous tumour rupture as independent predictors of survival and integrated them into a nomogram model. The nomogram's ability to forecast survival at 1, 3, and 5 years was subsequently confirmed with high concordance using an internal ...

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,...

En Perú, el carcinoma hepatocelular (CHC) ocupa el tercer lugar en incidencia entre los tumores del sistema digestivo, y tiene una alta tasa de mortalidad, 17.7 por 100,000 habitantes. La mayoría de los casos reportados no presentan la epidemiología clínica clásica del CHC observado en otras partes del mundo. Además, se ha identificado que estos pacientes presentan un perfil transcriptómico distinto y un proceso tumoral singular, sugiriendo un proceso particular de hepatocarcinogénesis en una fracción de la población peruana. El presente estudio busca comprender la implicancia clínica y biológica del perfil epigenético (metilación) y de expresión de los genes (transcriptómico) del CHC en los pacientes peruanos. Se evaluó el perfil de transcriptómico y de metilación de ADN de hígado y CHC en 74 pacientes peruanos. El agrupamiento por edades mostró una mayor metilació...

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 str...

Background: Liver resection is the mainstay treatment option for patients with hepatocellular carcinoma in the non-cirrhotic liver (NCL-HCC), but almost half of these patients will experience a recurrence within five years of surgery. Therefore, we aimed to develop a rationale-based risk evaluation tool to assist surgeons in recurrence-related treatment planning for NCL-HCC. Methods: We analyzed single-center data from 263 patients who underwent liver resection for NCL-HCC. Using machine learning modeling, we first determined an optimal cut-off point to discriminate early versus late relapses based on time to recurrence. We then constructed a risk score based on preoperative variables to forecast outcomes according to recurrence-free survival. Results: We computed an optimal cut-off point for early recurrence at 12 months post-surgery. We identified macroscopic vascular invasion, multifo...

The Central Andes of Peru are a region of great concern regarding pesticide risk to the health of local communities. Therefore, we conducted an observational study to assess the level of pesticide contamination among Andean people. Analytical chemistry methods were used to measure the concentrations of 170 pesticide-related compounds in hair samples from 50 adult Andean subjects living in rural and urban areas. As part of the study, a questionnaire was administered to the subjects to collect information regarding factors that increase the risk of pesticide exposure. Our results indicate that Andean people are strongly exposed to agrochemicals, being contaminated with a wide array of pesticide-related compounds at high concentration levels. Multivariate analyses and geostatistical modeling identified sociodemographic factors associated with rurality and food origin that increase pesticide...

This study was funded by the French National Alliance for Life Sciences and Health (ENV201408); LC was a recipient of a doctoral fellowship from French National Research Institute for Sustainable Development (IRD) (EMHE-ARTS-2016-878573B); JPC was a recipient of a doctoral fellowship from the Peruvian National Council for Science and Technology (212-2015-FONDECYT); SB has received funding from the European Union’s Horizon 2020 Framework program under the Marie Sk?odowska-Curie Actions 823935 and from the Alliance pour les Sciences de la Vie et de la Santé (AVIESAN), ITMO Cancer ENV201408, and LC, ER, and SCZ have received funding from the World Bank Group and FONDECYT-CONCYTEC 016-2018-FONDECYT/BM. The authors are grateful to Karina Cancino, Danny Cordova (INEN Cancer Research Biobank), Patricia Leroyer (NUMECAN), Alain Fautrel, Marine Seffals, Gevorg Ghukasyan (H2P2 platform). They a...