Gene Expression Profiles of Non-Small Cell Lung Cancer: Survival Prediction and New Biomarkers

Objectives: Despite the well-defined histological types of non-small cell lung cancer (NSCLC), a given stage is often associated with wide-ranging survival rates and treatment outcomes. This disparity has led to an increased demand for the discovery and identification of new informative biomarkers. Methods: In the current study, we screened 81 NSCLC samples using Illumina® whole-genome gene expression microarrays in an effort to identify differentially expressed genes and new NSCLC biomarkers. Results: We identified novel genes whose expression was upregulated in NSCLC, including SPAG5, POLH, KIF23, and RAD54L, which are associated with mitotic spindle formation, DNA repair, chromosome segregation, and dsDNA break repair, respectively. We also identified several novel genes whose expression was downregulated in NSCLC, including SGCG, NLRC4, MMRN1, and SFTPD, which are involved in extracellular matrix formation, apoptosis, blood vessel leakage, and inflammation, respectively. We found a significant correlation between RNA degradation and survival in adenocarcinoma cases. Conclusions: Even though the follow-up time was too limited to draw final conclusions, we were able to show better prediction p values in a group selection based on molecular profiles compared to histology. The current study also uncovered new candidate biomarker genes that are likely to be involved in diverse processes associated with NSCLC development.

[1]  Jens Gruber,et al.  The mitotic-spindle-associated protein astrin is essential for progression through mitosis , 2002, Journal of Cell Science.

[2]  M. Albertella,et al.  A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. , 2005, Cancer research.

[3]  B. Dahlbäck,et al.  Identification of the MMRN1 Binding Region within the C2 Domain of Human Factor V* , 2004, Journal of Biological Chemistry.

[4]  Hedi Peterson,et al.  g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments , 2007, Nucleic Acids Res..

[5]  T. Kundu,et al.  Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis , 2005, Oncogene.

[6]  J. Bertin,et al.  Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. , 2001, Biochemical and biophysical research communications.

[7]  E. Nigg,et al.  Astrin is required for the maintenance of sister chromatid cohesion and centrosome integrity , 2007, The Journal of cell biology.

[8]  Gordon K Smyth,et al.  Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2004, Statistical applications in genetics and molecular biology.

[9]  I. König,et al.  Association of polymorphisms in the human surfactant protein‐D (SFTPD) gene and postnatal pulmonary adaptation in the preterm infant , 2009, Acta paediatrica.

[10]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[11]  K. Bushby,et al.  Sarcoglycanopathies: Can muscle immunoanalysis predict the genotype? , 2008, Neuromuscular Disorders.

[12]  Yuh‐Cheng Yang,et al.  Silencing of astrin induces the p53-dependent apoptosis by suppression of HPV18 E6 expression and sensitizes cells to paclitaxel treatment in HeLa cells. , 2006, Biochemical and biophysical research communications.

[13]  Vedrana Milinkovic,et al.  Identification of genes associated with non-small-cell lung cancer promotion and progression. , 2010, Lung cancer.

[14]  Z. Ram,et al.  The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain , 2009, Clinical Cancer Research.

[15]  Roger Woodgate,et al.  Xeroderma pigmentosum-variant patients from America, Europe, and Asia. , 2008, The Journal of investigative dermatology.

[16]  T. Nagano,et al.  Four types of possible founder mutations are responsible for 87% of Japanese patients with Xeroderma pigmentosum variant type. , 2008, Journal of dermatological science.

[17]  T. D’amico.  Molecular biologic staging of lung cancer. , 2008, The Annals of thoracic surgery.

[18]  K. Kerr,et al.  Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  B. Passlick,et al.  Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study. , 2004, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[20]  A. Lophatananon,et al.  Comprehensive analysis of DNA repair gene variants and risk of meningioma. , 2008, Journal of the National Cancer Institute.

[21]  D. Lin,et al.  Expression of targeting protein for xklp2 associated with both malignant transformation of respiratory epithelium and progression of squamous cell lung cancer. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  H. Hansen,et al.  Lung cancer. , 1990, Cancer chemotherapy and biological response modifiers.

[23]  U. Klein,et al.  Cooperation between Mitotic Kinesins Controls the Late Stages of Cytokinesis , 2006, Current Biology.

[24]  J. Miller,et al.  Platelet adhesion to multimerin 1 in vitro: influences of platelet membrane receptors, von Willebrand factor and shear , 2009, Journal of thrombosis and haemostasis : JTH.

[25]  W. Travis,et al.  The new World Health Organization classification of lung tumours , 2001, European Respiratory Journal.

[26]  C. Mountain,et al.  The international system for staging lung cancer. , 2000, Seminars in surgical oncology.

[27]  G. Nicolaes,et al.  Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation , 2008, Thrombosis and Haemostasis.

[28]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[29]  Jun Liu,et al.  DNA Repair Gene Polymorphisms and Risk of Pancreatic Cancer , 2009, Clinical Cancer Research.

[30]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[31]  A. Sarasin,et al.  Role of DNA Polymerase η in the UV Mutation Spectrum in Human Cells* , 2003, Journal of Biological Chemistry.

[32]  T. Golub,et al.  Genome-wide views of cancer. , 2001, The New England journal of medicine.

[33]  G. Snyder,et al.  Surfactant protein D is expressed and modulates inflammatory responses in human coronary artery smooth muscle cells. , 2008, American journal of physiology. Heart and circulatory physiology.

[34]  Lea-Yea Chuang,et al.  RNA Silencing of Cks1 Induced G2/M Arrest and Apoptosis in Human Lung Cancer Cells , 2005, IUBMB life.

[35]  D. Henson,et al.  Conditional survival among patients with carcinoma of the lung. , 1999, Chest.

[36]  P. Woll,et al.  Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer , 2006, British Journal of Cancer.

[37]  Yuh Cheng Yang,et al.  Cloning and characterization of hMAP126, a new member of mitotic spindle-associated proteins. , 2001, Biochemical and biophysical research communications.

[38]  F. Hanaoka,et al.  Rad54 dissociates homologous recombination intermediates by branch migration , 2007, Nature Structural &Molecular Biology.

[39]  S. Lam,et al.  Surfactant protein D and bronchial dysplasia in smokers at high risk of lung cancer. , 2008, Chest.

[40]  K Bebenek,et al.  Error rate and specificity of human and murine DNA polymerase eta. , 2001, Journal of molecular biology.

[41]  Y. Terada,et al.  CHO1, a mammalian kinesin-like protein, interacts with F-actin and is involved in the terminal phase of cytokinesis , 2002, The Journal of cell biology.