A Five-Gene and Corresponding Protein Signature for Stage-I Lung Adenocarcinoma Prognosis

Purpose: Identification of effective markers for outcome is expected to improve the clinical management of non–small cell lung cancer (NSCLC). Here, we assessed in NSCLC the prognostic efficacy of genes, which we had previously found to be differentially expressed in an in vitro model of human lung carcinogenesis. Experimental Design: Prediction algorithms and risk-score models were applied to the expression of the genes in publicly available NSCLC expression data sets. The prognostic capacity of the immunohistochemical expression of proteins encoded by these genes was also tested using formalin-fixed paraffin-embedded (FFPE) tissue specimens from 156 lung adenocarcinomas and 79 squamous cell carcinomas (SCCs). Results: The survival of all-stages (P < 0.001, HR = 2.0) or stage-I (P < 0.001, HR = 2.84) adenocarcinoma patients that expressed the five-gene in vitro lung carcinogenesis model (FILM) signature was significantly poorer than that of patients who did not. No survival differences were observed between SCCs predicted to express or lack FILM signature. Moreover, all stages (P < 0.001, HR = 1.95) or stage-I (P = 0.001, HR = 2.6) adenocarcinoma patients predicted to be at high risk by FILM transcript exhibited significantly worse survival than patients at low risk. Furthermore, the corresponding protein signature was associated with poor survival (all stages, P < 0.001, HR = 3.6; stage-I, P < 0.001, HR = 3.5; stage-IB, P < 0.001, HR = 4.6) and mortality risk (all stages, P = 0.001, HR = 4.0; stage-I, P = 0.01, HR = 3.4; stage-IB, P < 0.001, HR = 7.2) in lung adenocarcinoma patients. Conclusions: Our findings highlight a gene and corresponding protein signature with effective capacity for identification of stage-I lung adenocarcinoma patients with poor prognosis that are likely to benefit from adjuvant therapy. Clin Cancer Res; 17(6); 1490–501. ©2010 AACR.

[1]  Viji M. Draviam,et al.  Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities , 2007, Nature.

[2]  Luis Serrano,et al.  Correlation of mRNA and protein in complex biological samples , 2009, FEBS letters.

[3]  Yi Zhang,et al.  Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. , 2006, Cancer research.

[4]  N. Hayward,et al.  Gene Expression Signature Predicts Recurrence in Lung Adenocarcinoma , 2007, Clinical Cancer Research.

[5]  David M Jablons,et al.  Genomic prognostic models in early-stage lung cancer. , 2009, Clinical lung cancer.

[6]  Jeremy J. W. Chen,et al.  A five-gene signature and clinical outcome in non-small-cell lung cancer. , 2007, The New England journal of medicine.

[7]  James Lee,et al.  Covariance adjustment of survival curves based on Cox's proportional hazards regression model , 1992, Comput. Appl. Biosci..

[8]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[9]  Diane D. Liu,et al.  Loss and Reduction of Fus1 Protein Expression is a Frequent Phenomenon in the Pathogenesis of Lung Cancer , 2008, Clinical Cancer Research.

[10]  Luc Girard,et al.  Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer , 2003, Oncogene.

[11]  S. Thorgeirsson,et al.  A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells , 2006, Nature Medicine.

[12]  Richard Simon,et al.  Gene expression-based prognostic signatures in lung cancer: ready for clinical use? , 2010, Journal of the National Cancer Institute.

[13]  M. Saraste,et al.  FEBS Lett , 2000 .

[14]  John D Minna,et al.  New molecularly targeted therapies for lung cancer. , 2007, The Journal of clinical investigation.

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

[16]  R. Lotan,et al.  Identification of Gene Signatures and Molecular Markers for Human Lung Cancer Prognosis using an In vitro Lung Carcinogenesis System , 2009, Cancer Prevention Research.

[17]  Richard Simon,et al.  What should physicians look for in evaluating prognostic gene-expression signatures? , 2010, Nature Reviews Clinical Oncology.

[18]  B. Shen,et al.  Disruption of the FEN-1/PCNA Interaction Results in DNA Replication Defects, Pulmonary Hypoplasia, Pancytopenia, and Newborn Lethality in Mice , 2007, Molecular and Cellular Biology.

[19]  Masahiro Tsuboi,et al.  The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer. , 2007, Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia.

[20]  M. Tyers,et al.  Molecular profiling of non-small cell lung cancer and correlation with disease-free survival. , 2002, Cancer research.

[21]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[22]  N. Hayward,et al.  Expression profiling defines a recurrence signature in lung squamous cell carcinoma. , 2006, Carcinogenesis.

[23]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[24]  E. Gabrielson.  Worldwide trends in lung cancer pathology , 2006, Respirology.

[25]  C. Ball,et al.  Identification of genes periodically expressed in the human cell cycle and their expression in tumors. , 2002, Molecular biology of the cell.

[26]  M. Kirschner,et al.  Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation , 2007, Nature.

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

[28]  Zhong Zheng,et al.  DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. , 2007, The New England journal of medicine.

[29]  Zhifu Sun,et al.  A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer , 2006, PLoS medicine.

[30]  G. Bepler,et al.  MCM2 - a promising marker for premalignant lesions of the lung: a cohort study , 2001, BMC Cancer.

[31]  R. Metcalf,et al.  A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. Quint.  Staging non-small cell lung cancer* , 2007, Cancer imaging : the official publication of the International Cancer Imaging Society.

[33]  S. Mukherjee,et al.  Retraction: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-80. , 2011, The New England journal of medicine.

[34]  Xianglin Shi,et al.  Constructing Molecular Classifiers for the Accurate Prognosis of Lung Adenocarcinoma , 2006, Clinical Cancer Research.

[35]  E. Marcotte,et al.  Global signatures of protein and mRNA expression levelsw , 2009 .

[36]  R. Lotan,et al.  Expression of Interleukin-1 Receptor–Associated Kinase-1 in Non–Small Cell Lung Carcinoma and Preneoplastic Lesions , 2009, Clinical Cancer Research.

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

[38]  D. Botstein,et al.  Diversity of gene expression in adenocarcinoma of the lung , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  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.

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

[41]  Igor Jurisica,et al.  Gene expression–based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study , 2008, Nature Medicine.

[42]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[43]  S. Lippman,et al.  Lung cancer. , 2008, The New England journal of medicine.

[44]  C. Sotiriou,et al.  Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures , 2007, Breast Cancer Research.

[45]  P. Hall,et al.  Fen1 expression: a novel marker for cell proliferation , 1998, The Journal of pathology.

[46]  Yingdong Zhao,et al.  Analysis of Gene Expression Data Using BRB-Array Tools , 2007, Cancer informatics.

[47]  S. Mukherjee,et al.  A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. , 2006, The New England journal of medicine.