6533b7d9fe1ef96bd126d671

RESEARCH PRODUCT

Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis

Vito BarbieriSerafino ConfortiEleonora IulianoPierosandro TagliaferriMaria Teresa Di MartinoCirino BottaFrancesca SciontiPietro Hiram GuzziMariamena ArbitrioMario CannataroMario CannataroStefania CodispotiPierfrancesco TassonePierfrancesco TassoneEmanuela AltomareGiuseppe Agapito

subject

0301 basic medicineOncologyMaleCancer ResearchLung Neoplasmsgenetic structuresMicroarrayPharmacologyToxicologySkin rash.0302 clinical medicineNon-small cell lung cancerCarcinoma Non-Small-Cell LungGenotypePharmacology (medical)Erlotinib HydrochlorideCholecalciferolOligonucleotide Array Sequence AnalysisSkin rashMiddle AgedOncologyErlotinib030220 oncology & carcinogenesisFemaleErlotinibDrug Eruptionsmedicine.drugmedicine.medical_specialtyGenotypeSingle-nucleotide polymorphismAntineoplastic AgentsPolymorphism Single Nucleotide03 medical and health sciencesErlotinib HydrochlorideInternal medicinemedicineHumansLung cancerAgedRetrospective StudiesPharmacology25-Hydroxyvitamin D3 1-alpha-HydroxylaseInflammationbusiness.industryMicroarray analysis techniquesCancerSingle nucleotide polymorphismsmedicine.diseaseSingle nucleotide polymorphism030104 developmental biologyDMETQuality of Lifebusiness

description

Purpose: 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. Methods: 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)®. Results: 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. Conclusion: 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.

yearjournalcountryeditionlanguage
2016-01-01
10.1007/s00280-015-2916-3http://hdl.handle.net/10447/512516