KRAS mutant allele-specific imbalance in lung adenocarcinoma

Mod Pathol. 2011 Dec;24(12):1571-7. doi: 10.1038/modpathol.2011.109. Epub 2011 Jul 8.


The significance of KRAS mutant allele-specific imbalance (MASI) in lung adenocarcinomas is unknown. KRAS MASI was defined as predominance of the mutant allele over the wild-type allele. We assessed the frequency of KRAS MASI by comparing peak heights of mutant and wild-type alleles on sequencing electropherograms and by KRAS fluorescence in situ hybridization (FISH). A review of sequencing electropherograms of 207 KRAS-mutated lung adenocarcinomas demonstrated 23 (11%) cases with the mutant allele peak higher than the wild-type allele peak and 15 (7%) cases with the mutant allele peak equal to the wild-type allele peak. Of 17 cases with the mutant allele peak higher or equal to the wild-type allele peak, 8 (47%) showed KRAS amplification by FISH. KRAS FISH analysis of 36 KRAS-mutated lung adenocarcinomas with the mutant allele peak lower than the wild-type allele peak, 21 KRAS and EGFR wild-type and 16 EGFR-mutated adenocarcinomas showed no KRAS amplification. KRAS MASI was associated with selective amplification of the KRAS mutant allele (P<0.001). Patients with KRAS MASI showed worse overall survival. The cumulative proportion surviving at 17 months for KRAS MASI group was 35% compared with 84.1% for patients with KRAS mutant allele peak lower than wild-type allele peak (P=0.012). The adverse prognostic significance of KRAS MASI was independent of clinical stage and was maintained among stage I patients. The detection of KRAS MASI in lung adenocarcinomas by sequencing electropherograms may identify patients with more aggressive disease.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Aged
  • Allelic Imbalance*
  • Biomarkers, Tumor / genetics*
  • DNA Mutational Analysis
  • ErbB Receptors / genetics
  • Female
  • Gene Amplification
  • Genetic Predisposition to Disease
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Mutation*
  • Neoplasm Staging
  • Phenotype
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Time Factors
  • ras Proteins / genetics*


  • Biomarkers, Tumor
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins