Integrated molecular portrait of non-small cell lung cancers

BackgroundNon-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC.MethodsComparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC.ResultsAt DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944.ConclusionsIntegrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

[1]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[2]  Seungbok Lee,et al.  A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. , 2012, Genome research.

[3]  S. Dacic,et al.  Genomic pathology: challenges for implementation. , 2011, Archives of pathology & laboratory medicine.

[4]  Ming You,et al.  MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer. , 2012, Carcinogenesis.

[5]  G. Silvestri,et al.  One hundred years of lung cancer. , 2005, American journal of respiratory and critical care medicine.

[6]  C. Henschke,et al.  The Use of Genetic Markers to Identify Lung Cancer in Fine Needle Aspiration Samples , 2008, Clinical Cancer Research.

[7]  A. Borczuk,et al.  Expression profiling and lung cancer development. , 2007, Proceedings of the American Thoracic Society.

[8]  Il-Jin Kim,et al.  Gremlin is Overexpressed in Lung Adenocarcinoma and Increases Cell Growth and Proliferation in Normal Lung Cells , 2012, PloS one.

[9]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[10]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[11]  Andrey Alexeyenko,et al.  Network enrichment analysis: extension of gene-set enrichment analysis to gene networks , 2012, BMC Bioinformatics.

[12]  Lee Woojoo,et al.  Sparse Canonical Covariance Analysis for High-throughput Data , 2011 .

[13]  The eMERGE Clinical Annotation Working Group,et al.  Expression profiling — best practices for data generation and interpretation in clinical trials , 2004 .

[14]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[15]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[16]  D. Pe’er,et al.  An Integrated Approach to Uncover Drivers of Cancer , 2010, Cell.

[17]  F Levi,et al.  European cancer mortality predictions for the year 2012. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[18]  J. Koo,et al.  EGFR and HER-2 status of non-small cell lung cancer brain metastasis and corresponding primary tumor. , 2011, Neoplasma.

[19]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[20]  C. la Vecchia,et al.  European cancer mortality predictions for the year 2011. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  H. Izumi,et al.  NDRG1/Cap43/Drg-1 may Predict Tumor Angiogenesis and Poor Outcome in Patients with Lung Cancer , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[22]  D. Kell.  BMC Medical Genomics , 2008 .

[23]  G. Fontanini,et al.  Osteopontin Expression and Prognostic Significance in Non–Small Cell Lung Cancer , 2005, Clinical Cancer Research.

[24]  Agus Salim,et al.  Identification of recurrent regions of copy-number variants across multiple individuals , 2009, BMC Bioinformatics.

[25]  H. Sasaki,et al.  Expression of the sensitive to apoptosis gene, SAG, as a prognostic marker in nonsmall cell lung cancer , 2001, International journal of cancer.

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

[27]  K. Einarsdóttir,et al.  Department of Medical Epidemiology and Biostatistics, , 2007 .

[28]  M. Martinka,et al.  Aberrant Expression of Collagen Triple Helix Repeat Containing 1 in Human Solid Cancers , 2006, Clinical Cancer Research.

[29]  Angela N. Brooks,et al.  Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing , 2012, Cell.

[30]  F Levi,et al.  Lung cancer mortality in European women: recent trends and perspectives. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[31]  M. Rapellino,et al.  Tumor-associated trypsin inhibitor (TATI) in the diagnosis of lung cancer. , 1991, Scandinavian journal of clinical and laboratory investigation. Supplementum.

[32]  Yoo Jin Jung,et al.  The transcriptional landscape and mutational profile of lung adenocarcinoma , 2012, Genome research.

[33]  Guidel Ines,et al.  Expression profiling — best practices for data generation and interpretation in clinical trials , 2004, Nature Reviews Genetics.

[34]  A. V. López-Malpartida,et al.  Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. , 2009, Lung cancer.

[35]  Anbupalam Thalamuthu,et al.  Multi-platform segmentation for joint detection of copy number variants , 2011, Bioinform..

[36]  Y. Pawitan,et al.  Modified least-variant set normalization for miRNA microarray. , 2010, RNA: A publication of the RNA Society.

[37]  J. Kim,et al.  Gremlin-1 Induces BMP-Independent Tumor Cell Proliferation, Migration, and Invasion , 2012, PloS one.

[38]  J. Orenstein,et al.  Revolution in lung cancer: new challenges for the surgical pathologist. , 2012, Archives of pathology & laboratory medicine.

[39]  W. Jiang,et al.  Expression of bone morphogenetic protein 7 in lung cancer and its biological impact on lung cancer cells. , 2010, Anticancer research.

[40]  Chris Sander,et al.  An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors , 2009, Oncogene.

[41]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[42]  G. da Cunha Santos,et al.  EGFR gene status in cytological samples of nonsmall cell lung carcinoma , 2011, Cancer cytopathology.

[43]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.