Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience

J Thorac Oncol. 2015 May;10(5):768-777. doi: 10.1097/JTO.0000000000000516.

Abstract

Introduction: Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing and clinicopathologic correlations are presented.

Methods: Mutation testing in at least one of the eight genes (epidermal growth factor receptor [EGFR], KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, and PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing+/- peptide nucleic acid and/or sizing assays, along with anaplastic lymphoma kinase (ALK) and/or MET fluorescence in situ hybridization, were performed in six labs on 1007 patients from 14 institutions.

Results: In all, 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared with 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22%, 25%, 8.5%, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never-smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never-smoking status and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never-smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK, or MET.

Conclusion: Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / secondary
  • Adrenal Gland Neoplasms / genetics*
  • Adrenal Gland Neoplasms / secondary
  • Anaplastic Lymphoma Kinase
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / secondary
  • Class I Phosphatidylinositol 3-Kinases
  • Continental Population Groups / genetics
  • Cooperative Behavior
  • DNA Mutational Analysis / methods
  • DNA Mutational Analysis / standards
  • Female
  • Gene Rearrangement
  • Genes, erbB-1 / genetics
  • Genes, erbB-2 / genetics
  • Genes, ras / genetics
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / secondary
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • MAP Kinase Kinase 1 / genetics
  • Male
  • Mutation
  • Neoplasm Staging
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-met / genetics
  • Receptor Protein-Tyrosine Kinases / genetics
  • Sex Factors
  • Smoking / genetics

Substances

  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 1