title: Proteomic profiling of lung adenocarcinoma indicates heightened DNA repair, antioxidant mechanisms and identifies LASP1 as a potential negative predictor of survival.
abstract: BACKGROUND
  Lung cancer is the leading cause of cancer mortality in the United States. Non-small cell lung cancer accounts for 85% of all lung cancers for which adenocarcinoma is the most common histological type. Management of lung cancer is hindered by high false-positive rates due to difficulty resolving between benign and malignant tumors. Better molecular analysis comparing malignant and non-malignant tissues will provide important evidence of the underlying biology contributing to tumorigenesis.
  
  
  METHODS
  We utilized a proteomics approach to analyze 38 malignant and non-malignant paired tissue samples obtained from current or former smokers with early stage (Stage IA/IB) lung adenocarcinoma. Statistical mixed effects modeling and orthogonal partial least squares discriminant analysis were used to identify key cancer-associated perturbations in the adenocarcinoma proteome. Identified proteins were subsequently assessed against clinicopathological variables.
  
  
  RESULTS
  Top cancer-associated protein alterations were characterized by: (1) elevations in APEX1, HYOU1 and PDIA4, indicative of increased DNA repair machinery and heightened anti-oxidant defense mechanisms; (2) increased LRPPRC, STOML2, COPG1 and EPRS, suggesting altered tumor metabolism and inflammation; (3) reductions in SPTB, SPTA1 and ANK1 implying dysregulation of membrane integrity; and (4) decreased SLCA41 suggesting altered pH regulation. Increased protein levels of HYOU1, EPRS and LASP1 in NSCLC adenocarcinoma was independently validated by tissue microarray immunohistochemistry. Immunohistochemistry for HYOU1 and EPRS indicated AUCs of 0.952 and 0.841, respectively, for classifying tissue as malignant. Increased LASP1 correlated with poor overall survival (HR 3.66 per unit increase; CI 1.37-9.78; p = 0.01).
  
  
  CONCLUSIONS
  These results reveal distinct proteomic changes associated with early stage lung adenocarcinoma that may be useful prognostic indicators and therapeutic targets.
authors: University of California, Davis Genome Center, Davis, CA USA.|Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX USA.
authors: Johannes F
authors: JF
authors: Fahrmann
authors: CDS Creative Data Solutions, Ballwin, MO USA.
authors: Dmitry
authors: D
authors: Grapov
authors: Genome Center Proteomics Core Facility, University of California, Davis, Davis, CA USA.
authors: Brett S
authors: BS
authors: Phinney
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis Medical Center, 4501 X Street, Suite 3016, Sacramento, CA 95817 USA.
authors: Carol
authors: C
authors: Stroble
authors: University of California, Davis Genome Center, Davis, CA USA.
authors: Brian C
authors: BC
authors: DeFelice
authors: Division of Pulmonary, Critical Care, and Sleep, NYU School of Medicine, New York, NY USA.
authors: William
authors: W
authors: Rom
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis Medical Center, 4501 X Street, Suite 3016, Sacramento, CA 95817 USA.
authors: David R
authors: DR
authors: Gandara
authors: Department of Pathology and Laboratory Medicine, University of California, Davis Medical Center, Sacramento, CA USA.
authors: Yanhong
authors: Y
authors: Zhang
authors: University of California, Davis Genome Center, Davis, CA USA.|Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia.
authors: Oliver
authors: O
authors: Fiehn
authors: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York City, NY USA.
authors: Harvey
authors: H
authors: Pass
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis Medical Center, 4501 X Street, Suite 3016, Sacramento, CA 95817 USA.
authors: Suzanne
authors: S
authors: Miyamoto
keywords: Biomarker; Lung adenocarcinoma; Proteomics