title: Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy.
authors.forename: Mariamena
authors.initials: M
authors.lastname: Arbitrio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.affiliation: Medical Oncology Unit, Mater Domini Hospital, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Barbieri
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Agapito
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Pietro Hiram
authors.initials: PH
authors.lastname: Guzzi
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Iuliano
authors.affiliation: Department of Pediatrics, Magna Graecia University, Catanzaro, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Scionti
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Altomare
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Codispoti
authors.affiliation: Medical Oncology Unit, Mariano Santo Hospital, Cosenza, Italy.
authors.forename: Serafino
authors.initials: S
authors.lastname: Conforti
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.|ICAR-CNR, Cosenza, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cannataro
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.|Medical Oncology Unit, Mater Domini Hospital, Salvatore Venuta University Campus, Catanzaro, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy. pierosandrotagliaferri@gmail.com.|Medical Oncology Unit, Mater Domini Hospital, Salvatore Venuta University Campus, Catanzaro, Italy. pierosandrotagliaferri@gmail.com.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002762:Cholecalciferol / Q000378:metabolism; D003875:Drug Eruptions / Q000209:etiology* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011788:Quality of Life; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D002762:Cholecalciferol; D000069347:Erlotinib Hydrochloride; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: DMET; Erlotinib; Non-small cell lung cancer; Single nucleotide polymorphisms; Skin rash