title: Characterizing the molecular spatial and temporal field of injury in early-stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling.
abstract: Gene expression alterations in response to cigarette smoke have been characterized in normal-appearing bronchial epithelium of healthy smokers, and it has been suggested that adjacent histologically normal tissue displays tumor-associated molecular abnormalities. We sought to delineate the spatial and temporal molecular lung field of injury in smoker patients with early-stage non-small cell lung cancer (NSCLC; n = 19) who were accrued into a surveillance clinical trial for annual follow-up and bronchoscopies within 1 year after definitive surgery. Bronchial brushings and biopsies were obtained from six different sites in the lung at the time of inclusion in the study and at 12, 24, and 36 months after the first time point. Affymetrix Human Gene 1.0 ST arrays were used for whole-transcript expression profiling of airways (n = 391). Microarray analysis identified gene features (n = 1,165) that were nonuniform by site and differentially expressed between airways adjacent to tumors relative to more distant samples as well as those (n = 1,395) that were significantly altered with time up to 3 years. In addition, gene interaction networks mediated by phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK)1/2 were modulated in adjacent compared with contralateral airways and the latter network with time. Furthermore, phosphorylated AKT and ERK1/2 immunohistochemical expression were significantly increased with time (nuclear pAKT, P = 0.03; cytoplasmic pAKT, P < 0.0001; pERK1/2, P = 0.02) and elevated in adjacent compared with more distant airways (nuclear pAKT, P = 0.04; pERK1/2, P = 0.03). This study highlights spatial and temporal cancer-associated expression alterations in the molecular field of injury of patients with early-stage NSCLCs after definitive surgery that warrant further validation in independent studies.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
authors.forename: Chi-Wan
authors.initials: CW
authors.lastname: Chow
authors.forename: Wenhua
authors.initials: W
authors.lastname: Lang
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Chu
authors.forename: Melinda
authors.initials: M
authors.lastname: Garcia
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kabbout
authors.forename: You-Hong
authors.initials: YH
authors.lastname: Fan
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Diane A
authors.initials: DA
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Gold
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000368:Aged; D001706:Biopsy; D001999:Bronchoscopy / Q000379:methods; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D055370:Lung Injury / Q000175:diagnosis / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases