Arbitrio Mariamena, Di Martino Maria Teresa, Barbieri Vito, Agapito Giuseppe, Guzzi Pietro Hiram, Botta Cirino, Iuliano Eleonora, Scionti Francesca, Altomare Emanuela, Codispoti Stefania, Conforti Serafino, Cannataro Mario, Tassone Pierfrancesco, Tagliaferri Pierosandro
ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy.
Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
Cancer Chemother Pharmacol. 2016 Jan;77(1):205-9. doi: 10.1007/s00280-015-2916-3. Epub 2015 Nov 25.
Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients.
In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA).
Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development.
Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level.
厄洛替尼是常用于晚期非小细胞肺癌（aNSCLC）的靶向药物。然而，药物相关的皮肤毒性常常会影响癌症患者的生活质量并导致治疗中断。药物转运体和代谢酶的基因多态性在厄洛替尼治疗的疗效和毒性个体差异中起主要作用。我们研究的目的是通过新型药物代谢酶和转运体（DMET）微阵列Affymetrix平台，在aNSCLC患者中确定影响皮疹（SR）的吸收、分布、代谢和排泄基因中的遗传决定因素。
在一项回顾性研究中，34例接受厄洛替尼治疗的aNSCLC患者通过DMET Plus芯片进行基因分型：23例患者出现SR（病例组），11例患者未出现（对照组）。对外周血DNA进行基因分型。通过Fisher精确检验分析基因型关联，并对毒性相关基因集进行 Ingenuity 通路分析（IPA）。
六个基因（CYP27B1、MAT1A1、CHST1、CYP4B1、ADH6和SLC22A1）中的七个单核苷酸多态性（SNP）与SR的发生或具有保护作用相关。具体而言，CYP27B1基因中的rs8176345与SR显著相关（p = 0.0003，OR 55.55，95% CI 2.7036 - 1141.1707）。对SR相关基因的IPA突出了多种经典通路的作用，包括1,25 - 二羟基维生素D3生物合成、S - 腺苷 - L - 甲硫氨酸生物合成和甲硫氨酸降解I（生成同型半胱氨酸）在SR发生中的作用。
尽管本研究具有探索性，但表明CYP27B1基因中的rs8176345与aNSCLC患者中厄洛替尼诱导的SR显著相关，可能是通过皮肤水平的维生素D3和炎症介导的机制。
