Abstract
BackgroundLung 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.MethodsWe 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.ResultsTop 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).ConclusionThese results reveal distinct proteomic changes associated with early stage lung adenocarcinoma that may be useful prognostic indicators and therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-016-9132-y) contains supplementary material, which is available to authorized users.
Highlights
Lung cancer is the leading cause of cancer mortality in the United States
While use of low dose computerized tomography (LDCT) for screening of persons at high risk for lung cancer can reduce cancer mortality, it is plagued by high false positive rates (96%) [5] because it is unable to adequately distinguish indolent solid pulmonary nodules (SPNs) from malignant SPNs
EPRS, HYOU1 and LASP1 from the discovery study were independently validated with a tissue microarray containing 40 pairs of malignant and non-malignant tissues from patients with early stage Non-small cell lung cancer (NSCLC) adenocarcinoma
Summary
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. While use of low dose computerized tomography (LDCT) for screening of persons at high risk for lung cancer can reduce cancer mortality, it is plagued by high false positive rates (96%) [5] because it is unable to adequately distinguish indolent (benign) solid pulmonary nodules (SPNs) from malignant SPNs. Increased knowledge of the molecular perturbations caused by tumorigenesis is needed to better understand the underlying biology, as well as potentially assisting with diagnosis, prognosis and identification of additional treatment targets. We hypothesize that identification of cancer induced cellular and tissue level protein changes will provide candidate tissue-specific prognostic markers for early stage adenocarcinoma that may eventually be used to better distinguish adenocarcinoma from benign tissues, help identify potential therapeutic targets for treatment of lung cancer and, importantly, improve our understanding of the mechanism(s) leading to lung cancer
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