Sanduzzi Zamparelli, Marco (2022) Polymorphism AGT2 (rs4762) is involved in development of dermatologic adverse events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Polymorphism AGT2 (rs4762) is involved in development of dermatologic adverse events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib.
Sanduzzi Zamparelli,
Date: 6 July 2022
Number of Pages: 71
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Clinica e Chirurgia
Dottorato: Terapie avanzate biomediche e chirurgiche
Ciclo di dottorato: 34
Coordinatore del Corso di dottorato:
Di Minno,
Morisco, FilomenaUNSPECIFIED
Date: 6 July 2022
Number of Pages: 71
Keywords: Hepatocellular carcinoma; systemic therapy; polymorphism; dermatologic adverse events.
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/12 - Gastroenterologia
Date Deposited: 12 Jul 2022 11:01
Last Modified: 28 Feb 2024 11:07

Collection description

Introduction: Dermatologic adverse events (DAEs) are associated to better outcome of patients with hepatocellular carcinoma (HCC) in a variety of tyrosine kinase inhibitors (TKIs) treatments. The exact mechanisms associated with the development of DAEs are unknown although several studies pointed to a possible direct skin-toxicity of TKIs 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. Objective: To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs. Methods: 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 (BCLC-1 cohort). Three additional cohorts were analyzed for AGT1 (rs699) and AGT2 (rs4762) polymorphisms - initially identified as predictors of DAEs: BCLC-2 (n=79), Northern Italy (n=221) and Naples (n=69) cohorts. The relation between SNPs and dermatological AEs (DAEs) and death were assessed by means of univariate and multivariate Cox regression models, and presented with hazard ratios and their 95% confidence intervals (95% CI). Results: The BCLC-1 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 the 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 risk of DAE development. Conclusion: DAE development in HCC patients receiving TKIs could be explained by AGT2 (rs4762) gene variant. If validated in other antioncogenic treatments, it might be envisioned as a good prognosis or predictive marker.


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