title: Higher dosage of the epidermal growth factor receptor mutant allele in lung adenocarcinoma correlates with younger age, stage IV at presentation, and poorer survival.
abstract: BACKGROUND
  The clinical significance of epidermal growth factor receptor (EGFR) mutant allele specific imbalance (MASI) in lung adenocarcinomas is unknown.
  
  
  METHODS
  EGFR MASI was characterized by sequencing electropherograms (SEs) and EGFR fluorescence in situ hybridization (FISH) in 96 prospectively tested lung adenocarcinoma patients with a median follow-up of 20 months (all cases were EGFR mutation-positive).
  
  
  RESULTS
  In 25 cases, the mutant allele (MA) peak was higher than the wild-type allele (WA) peak, indicating the presence of EGFR MASI (25/96, 26%). The adenocarcinomas with EGFR MASI had a 4.4-fold higher average EGFR/Chromosome Enumeration Probe 7 ratio than carcinomas without MASI (7.9 ± 3.8 versus 1.8 ± 0.6, p = 0.01). A high degree of correlation between the MA/WA ratio (SE) and the EGFR/CEP7 ratio (FISH) (ρ = 0.757, p = 0.003) validated the quantitative nature of SE. Amplification was the most common mechanism of EGFR MASI (13/21, 62%). EGFR MASI was more commonly associated with exon 19 mutations than with exon 21 mutations (19/53, 36%, versus 6/43, 14%, p = 0.015, odds ratio [OR] = 3.4) and in patients younger than 65 years (17/46, 37%, versus 8/50, 16%, p = 0.019, OR = 3.1). Patients with EGFR MASI presented with stage IV disease more frequently (p = 0.01, OR = 3.5) and had a poorer disease-specific survival rate (p = 0.021, 54% versus 83% at 31 months).
  
  
  CONCLUSIONS
  EGFR MASI in lung adenocarcinomas can be assessed based on SE and can be used to identify younger patients with more aggressive disease.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Oakley
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000367:Age Factors; D000368:Aged; D000483:Alleles; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D004273:DNA, Neoplasm; C512478:EGFR protein, human; D066246:ErbB Receptors