Genomic and transcriptional alterations in lung adenocarcinoma in relation to EGFR and KRAS mutation status

PLoS One. 2013 Oct 24;8(10):e78614. doi: 10.1371/journal.pone.0078614. eCollection 2013.

Abstract

Introduction: In lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression.

Methods: Genomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods.

Results: EGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities.

Conclusions: We provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma of Lung
  • DNA Copy Number Variations / genetics
  • ErbB Receptors / genetics*
  • Female
  • Genes, ras / genetics*
  • Genomics*
  • Humans
  • Lung Neoplasms / genetics*
  • Male
  • Mutation*
  • Transcription, Genetic*

Substances

  • ErbB Receptors

Grant support

Financial support for this study was provided by the Swedish Cancer Society, the Knut & Alice Wallenberg Foundation, the Foundation for Strategic Research through the Lund Centre for Translational Cancer Research (CREATE Health), the Mrs Berta Kamprad Foundation, the Gunnar Nilsson Cancer Foundation, the Swedish Research Council, the Lund University Hospital Research Funds, the Gustav V:s Jubilee Foundation, and the IngaBritt and Arne Lundberg Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.