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Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

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World Journal of Hepatology 2022年第7期14卷 1438-1458页

作者： Víctor Sapena Massimo Iavarone Loreto Boix Floriana Facchetti mar.a guarino marco Sanduzzi Zamparelli Alessandro Granito Esther Samper mario Scartozzi Josep Corominas Giorgia marisi Alba Díaz Andrea Casadei-Gardini Laura Gramantieri Pietro Lampertico Filomena Morisco Ferran Torres Jordi Bruix mar.a Reig Barcelona Clinic Liver Cancer Group Liver UnitHospital Clínic de BarcelonaInstitut d'Investigacions Biomèdiques August Pi SunyerCentro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelona 08036Spain Universidad de Barcelona Barcelona 08036Spain Division of Gastroenterology and Hepatology Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca’Granda Ospedale Maggiore PoliclinicoMilano 20122Italy Department of Clinical Medicine and Surgery Gastroenterology UnitUniversity of Naples Federico IINaples 80131Italy Gastroenterology and Hepatology Unit Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica CàGranda Ospedale Maggiore PoliclinicoUniversity of MilanMilan 20100Italy Department of Clinical Medicine and Surgery Gastroenterology UnitUniversity of Naples"Federico II"Napoli 80100Italy Department of Clinical Medicine and Surgery Gastroenterology and HepatologyFederico II University of NaplesNaples 80131Italy Division of Internal Medicine Hepatobiliary and Immunoallergic DiseasesIstituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero-Universitaria di BolognaBologna 40139Italy Department of Medical and Surgical Sciences University of BolognaBologna 40139Italy Department of Medical Oncology University of CagliariCagliari 45698Italy Biosciences Laboratory Istituto di Ricovero e Cura a Carattere Scientifico di Natura PubblicaIstituto Romagnolo per lo Studio dei Tumori“Dino Amadori”Meldola 47014Italy Department of Pathology Hospital Clínic de BarcelonaUniversitat de BarcelonaBarcelona 08036Spain School of Medicine Vita-Salute San Raffaele UniversityMilan 20132Italy Unit of Oncology UniversitàVita-SaluteIstituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica-San Raffaele Scientific InstituteMilan 20132Italy Division of Internal Medicine Hepatobiliary and Immunoallergic DiseasesIstituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Aziend

BACKGROUND Dermatologic adverse events(DAEs)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent *** exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic *** is the case in other conditions,individual genetic variants may partially explain a higher risk of *** To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with *** We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(AE)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAEs:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,*** relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).RESULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of ***,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAEs(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,ECOG-PS,diabetes and *** value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of D

关键词： HCC Early DAE Single-nucleotide polymorphisms AGT1(rs699) AGT2(rs4762),Tyrosine kinase inhibitors

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