title: High-throughput screening identified inherited genetic variations in the EGFR pathway contributing to skin toxicity of EGFR inhibitors.
abstract: OBJECTIVE
  To identify genomic variants in the EGFR pathway and in cytokines predisposing to skin toxicity from EGFR inhibitors.
  
  
  METHODS
  In 126 patients with cancer and EGFR inhibitor therapy skin toxicity was quantified and EGFR and inflammatory pathway genes were analyzed by deep sequencing.
  
  
  RESULTS
  We found 1437 SNPs in the 382-kb target region. Three SNPs in EGFR intron 1 were found exclusively in patients without skin rash. Another EGFR intron 23 SNP was associated with skin rash, overall survival and IL8 plasma concentrations. Moreover, carriers of the PIK3R1 326I variant were predisposed to skin rash and better survival.
  
  
  CONCLUSIONS
  Comprehensive pathway-based resequencing revealed some new but only moderately strong genomic predictors of skin toxicity.
authors.affiliation: Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
authors.forename: Sayed-Mohammad
authors.initials: SM
authors.lastname: Hasheminasab
authors.affiliation: Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
authors.forename: Mladen V
authors.initials: MV
authors.lastname: Tzvetkov
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schumann
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rüdiger
authors.affiliation: Department of Internal Medicine III & Comprehensive Cancer Center, Ludwig-Maximilian's University of Munich, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boeck
authors.affiliation: Department of Internal Medicine III & Comprehensive Cancer Center, Ludwig-Maximilian's University of Munich, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Private Practice for Hematology & Oncology, Ulm, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Kächele
authors.affiliation: Research Division, Federal Institute of Drugs & Medical Devices (BfArM), Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Research Division, Federal Institute of Drugs & Medical Devices (BfArM), Bonn, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Research Division, Federal Institute of Drugs & Medical Devices (BfArM), Bonn, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Hichert
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.affiliation: Research Division, Federal Institute of Drugs & Medical Devices (BfArM), Bonn, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects; D000068818:Cetuximab / Q000009:adverse effects; D003875:Drug Eruptions / Q000453:epidemiology / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007249:Inflammation / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; C508606:CXCL8 protein, human; D016209:Interleukin-8; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: EGFR; EGFR inhibitors; cetuximab; cytokines; erlotinib; high-throughput nucleotide sequencing; skin toxicity; targeted sequencing