Polymorphism AGT2 (rs4762) is involved in the development of dermatologic events : Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib
Sapena, Victor (Hospital Clínic i Provincial de Barcelona)
Iavarone, Massimo
Boix, Loreto (Hospital Clínic i Provincial de Barcelona)
Facchetti, Floriana
Guarino, Maria
Sanduzzi Zamparelli, Marco (Hospital Clínic i Provincial de Barcelona)
Granito, Alessandro
Samper, Esther (Hospital Clínic i Provincial de Barcelona)
Scartozzi, Mario
Corominas, Josep (Hospital Clínic i Provincial de Barcelona)
Marisi, Giorgia
Díaz, Alba (Hospital Clínic i Provincial de Barcelona)
Casadei-Gardini, Andrea
Gramantieri, Laura
Lampertico, Pietro
Morisco, Filomena
Torres, Ferran (Hospital Clínic i Provincial de Barcelona)
Bruix, Jordi (Hospital Clínic i Provincial de Barcelona)
Reig, María (Hospital Clínic i Provincial de Barcelona)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The 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 treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs. To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs. 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, respectively. The 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). 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 DAEs. Thereafter, 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 AHT. The 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 DAE development. DAE development in HCC patients receiving TKIs could be explained by the AGT2 (rs4762) gene variant. If validated in other anti-oncogenic treatments, it might be considered a good prognosis marker.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	AGT1 (rs699) ; AGT2 (rs4762) ; Early DAE ; HCC ; Single-nucleotide polymorphisms ; Tyrosine kinase inhibitors
Publicat a:	World Journal of Hepatology, Vol. 14 (july 2022) , p. 1438-1458, ISSN 1948-5182

DOI: 10.4254/wjh.v14.i7.1438
PMID: 36158918

22 p, 623.3 KB

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