Observational Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 27, 2022; 14(7): 1438-1458
Published online Jul 27, 2022. doi: 10.4254/wjh.v14.i7.1438
Polymorphism AGT2 (rs4762) is involved in the development of dermatologic events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib
Víctor Sapena, Massimo Iavarone, Loreto Boix, Floriana Facchetti, Maria 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, María Reig
Víctor Sapena, Loreto Boix, Marco Sanduzzi Zamparelli, Esther Samper, Josep Corominas, Alba Díaz, Jordi Bruix, María Reig, Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
Víctor Sapena, Marco Sanduzzi Zamparelli, Alba Díaz, Jordi Bruix, María Reig, Universidad de Barcelona, Barcelona 08036, Spain
Massimo Iavarone, Pietro Lampertico, Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca’ Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
Floriana Facchetti, Gastroenterology and Hepatology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan 20100, Italy
Maria Guarino, Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Napoli 80100, Italy
Marco Sanduzzi Zamparelli, Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology, Federico II University of Naples, Naples 80131, Italy
Alessandro Granito, Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero-Universitaria di Bologna, Bologna 40139, Italy
Alessandro Granito, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40139, Italy
Mario Scartozzi, Department of Medical Oncology, University of Cagliari, Cagliari 45698, Italy
Giorgia Marisi, Biosciences Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica, Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
Alba Díaz, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
Andrea Casadei-Gardini, School of Medicine, Vita-Salute San Raffaele University, Milan 20132, Italy
Andrea Casadei-Gardini, Unit of Oncology, Università Vita-Salute, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica-San Raffaele Scientific Institute, Milan 20132, Italy
Laura Gramantieri, Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero, Bologna 40138, Italy
Pietro Lampertico, Department of Pathophysiology and Transplantation, Colorectal Cancer “A. M. and A. Migliavacca” Center for Liver Disease, University of Milan, Milano 20122, Italy
Filomena Morisco, Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples Federico II, Naples 80131, Italy
Ferran Torres, Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona 08036, Spain
Ferran Torres, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Cerdanyola 08193, Spain
Author contributions: Reig M, Boix L, Iavarone M, Bruix J and Torres F designed the conceptualization; Reig M, Torres F and Sapena V performed the methodology; Sapena V and Torres F performed the formal analysis; Reig M, Boix L, Iavarone M, Bruix J and Sapena V performed the research; Sapena V and Sanduzzi Zamparelli M performed data curation; Sapena V, Boix L and Reig M wrote the original draft; Sapena V, Iavarone M, Boix L, Facchetti F, Guarino M, Sanduzzi Zamparelli M, Granito A, Samper E, Scartozzi M, Corominas J, Marisi G, Diaz A, Casadei-Gardini A, Gramantieri L, Lampertico P, Morisco F, Torres F, Bruix J, Reig M contributed analytic tools and reviewed and edited the manuscript; Reig M, Bruix J, Iavarone M and Morisco F performed expert supervision; Reig M and Iavarone M performed project administration; Reig M, Bruix J and Boix L searched funding acquisition.
Supported by the Bayer Grant, No. JBT-SOR 2013-01; the Instituto de Salud Carlos III, No. PI18/00768, PI15/00145 and PI18/0358; Fondo Europeo de Desarrollo Regional (FEDER) from the European Commission “Una manera de hacer Europa”; Pla estratègic de recerca i innovació en salut (PERIS) Grant, No. PERIS_IPIF19-SLT008/18/00182-RH0; Contratos Predoctorales de Formación en Investigación en Salud (PFIS), No. FI19/00222.
Institutional review board statement: The study was approved by the institutional review board of each center (HCB/2009/4755, HCB/2015/0352, Ethical Board 2 480_2018 and CE/2014/193).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Víctor Sapena: Travel grants from Bayer; Massimo Iavarone: Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, Guerbet, EISAI, Shionogi; Loreto Boix: Speaker fees from Bayer; Marco Sanduzzi Zamparelli: Speaker fees and travel funding from Bayer; Travel grant from BTG, Eisai and MSD; Mario Scartozzi: Speakers Bureau and Advisory board Bayer, EISAI, MSD, AMGEN, Merck, Sanofi; Alba Díaz: Speaker fees from Bayer; Andrea Casadei-Gardini: Speakers Bureau and Advisory board Bayer, EISAI, MSD, Ipsen, AstraZeneca, GSK; Pietro Lampertico: Speaking bureau/advisor for Abbvie, Eiger, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck/ Merck Sharp & Dohme, MYR Pharma, Roche; Ferran Torres: DSMB fees from Basilea Pharmaceutica International and ROVI; educational fees from Janssen and Ferrer; Jordi Bruix: Consultancy fees from Arqule, Bayer, Novartis, BMS, BTG-Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance/Onxeo, Roche, AbbVie, Merck, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, Basilea, Nerviano; Research grants from Bayer and BTG; Educational grants from Bayer and BTG; Lecture fees from Bayer, BTG-Biocompatibles, Eisai, Terumo, Sirtex, Ipsen; María Reig: Consultancy fees from Bayer, BMS, Roche, Ipsen, AstraZeneca, UniversalDX and Lilly; Lecture fees from Bayer, BMS, Gilead, Lilly and Roche; Research grants (to the institution) from Bayer, Roche and Ipsen; and the rest of the authors have no conflicts of interest to report.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: María Reig, PhD, Chief Physician, Research Scientist, Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Universidad de Barcelona, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Hospital Clínic, C/ Villarroel, 170, Escala 11, 4a planta, 08036 Barcelona, Spain. mreig1@clinic.cat
Received: November 9, 2021
Peer-review started: November 9, 2021
First decision: January 9, 2022
Revised: January 24, 2022
Accepted: July 6, 2022
Article in press: July 6, 2022
Published online: July 27, 2022
Processing time: 260 Days and 3.4 Hours
Core Tip

Core Tip: Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. Our study shows that DAE development in these patients can be explained by individual genetic variants in the AGT2 gene. AGT2 (rs4762) AA genotype was associated with DAE risk in the Northern Italy cohort and was externally validated in a cohort combining the BCLC1, BCLC2 and Naples cohorts. Therefore, DAE development in HCC patients receiving TKIs can be explained by the AGT2 (rs4762) gene variant. If validated in other anti-oncogenic treatments, it might be considered a good prognosis marker.