Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer

J Natl Cancer Inst. 2014 Mar;106(3):dju004. doi: 10.1093/jnci/dju004. Epub 2014 Feb 22.

Abstract

Background: Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC).

Methods: Whole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixed-effects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted.

Results: We identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P < .001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P < .05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P < .001) and promoted anchorage-dependent and -independent lung cancer cell growth.

Conclusions: The adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Non-Small-Cell Lung / diagnosis*
  • Carcinoma, Non-Small-Cell Lung / etiology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / etiology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Microarray Analysis
  • Middle Aged
  • Neoplasm Staging
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Real-Time Polymerase Chain Reaction / methods
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Vasoactive Intestinal Polypeptide, Type I / genetics
  • Smoking / adverse effects
  • Transcriptome*
  • Up-Regulation

Substances

  • LAPTM4B protein, human
  • Membrane Proteins
  • NETO2 protein, human
  • Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Receptors, Vasoactive Intestinal Polypeptide, Type I
  • VIPR1 protein, human
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II