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Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360569


Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is featured by an activation of interferon (IFN)-stimulated genes (ISGs; IFN signature), which we suppose is driven by type III IFNL4. Taking advantage of the TCGA collection of HCC patients of various different etiologies, this study aimed at validating our previous findings on hepatic IFNL4 gene activation in HCV infection in an independent and larger cohort of patients with advanced liver disease. In a cohort of n = 377 cases, the entirety of the sequencing data was used to assess the IFNL genotypes, and the cases were stratified for etiology. The number of IFNL4 transcripts within nonmalignant and malignant tissues was found to be more abundant in patients with HCV or HCV/HBV infections when compared to other risk factors. Moreover, in patients with HCV infection as a risk factor, a close, positive relationship was found between ISG activation and the number of functional IFNL4 transcripts. Data on this independent TCGA sample support the concept of an IFNL4-dependent HCV-driven activation of hepatic ISGs. In addition to that, they add to the understanding of etiology-related host immunological phenotypes in HCC.

Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Hepatite C Crônica/complicações , Interleucinas/metabolismo , Neoplasias Hepáticas/patologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Interleucinas/genética , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
BMC Cancer ; 20(1): 1131, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228589


BACKGROUND: Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are malignancies with a leading lethality. With reference to interferons (IFNs) known to mediate antitumor activities, this study investigated the relationship between germline genetic variations in type III IFN genes and cancer disease progression from The Cancer Genome Atlas (TCGA) data. The genetic variations under study tag a gain-or-loss-of-function dinucleotide polymorphism within the IFNL4 gene, rs368234815 [TT/ΔG]. METHODS: The entirety of the TCGA sequencing data was used to assess genotypes of 187 patients with HCC and of 162 patients with PDAC matched for ethnicity. Stratified for IFNL genotypes, both cohorts were subjected to time-to-event analyses according to Kaplan-Meier with regard to the length of the specific progression free interval (PFI) and the overall survival (OS) time as two clinical endpoints for disease progression. RESULTS: Logrank analysis revealed a significant relationship between IFNL genotypes and disease outcome for PDAC. This relationship was not found for HCC. A multiple Cox regression analysis employing patients' age, tumor grade and tumor stage as further covariates proved IFNL genotypes to be independent predictors for PDAC disease outcome. CONCLUSION: This repository-based approach unveiled clinical evidence suggestive for an impact of IFNL germline variations for PDAC progression with an IFNL haplotype predisposing for IFNL4 expression being favorable.

Adenocarcinoma/genética , Carcinoma Hepatocelular/genética , Carcinoma Ductal Pancreático/genética , Variação Genética/genética , Genoma/genética , Interferons/metabolismo , Interleucinas/metabolismo , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Progressão da Doença , Feminino , Células Germinativas , Humanos , Neoplasias Hepáticas/patologia , Masculino