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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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Polymorphism AGT2 (rs4762) is involved in development of dermatologic adverse events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib. |
| Autori: | Autore Email Sanduzzi Zamparelli, Marco msanduzzizamparelli@gmail.com |
| Data: | 6 Luglio 2022 |
| Numero di pagine: | 71 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Clinica e Chirurgia |
| Dottorato: | Terapie avanzate biomediche e chirurgiche |
| Ciclo di dottorato: | 34 |
| Coordinatore del Corso di dottorato: | nome email Di Minno, Giovanni diminno@unina.it |
| Tutor: | nome email Morisco, Filomena [non definito] |
| Data: | 6 Luglio 2022 |
| Numero di pagine: | 71 |
| Parole chiave: | Hepatocellular carcinoma; systemic therapy; polymorphism; dermatologic adverse events. |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/12 - Gastroenterologia |
| Depositato il: | 12 Lug 2022 11:01 |
| Ultima modifica: | 28 Feb 2024 11:07 |
| URI: | http://www.fedoa.unina.it/id/eprint/14372 |
Abstract
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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