title: Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer.
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.
authors.affiliation: Affiliations of authors: Department of Translational Molecular Pathology (HK, JF, TM, MMG, C-WC, ZC, GM, IIW), Department of Thoracic/Head and Neck Medical Oncology (MK, WKH, IIW), Department of Pathology (NK, CM), Department of Bioinformatics (S-YY, LS, JW, KRC), University of Texas MD Anderson Cancer Center, Houston, TX; Section of Computational Medicine, Department of Medicine, Boston University, Boston, MA (ACG, AS).
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Suk-Young
authors.initials: SY
authors.lastname: Yoo
authors.forename: Yuho
authors.initials: Y
authors.lastname: Maki
authors.forename: Adam C
authors.initials: AC
authors.lastname: Gower
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kabbout
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Garcia
authors.forename: Chi-Wan
authors.initials: CW
authors.lastname: Chow
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Chu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Mendoza
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Cesar
authors.initials: C
authors.lastname: Moran
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000235:genetics; D012907:Smoking / Q000009:adverse effects; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C477083:LAPTM4B protein, human; D008565:Membrane Proteins; C574595:NETO2 protein, human; D015513:Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II