Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to EGFR and KRAS Mutation Status

INTRODUCTION In lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression. METHODS Genomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods. RESULTS EGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities. CONCLUSIONS We provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.

[1]  Johan Staaf,et al.  Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome , 2013, Clinical Cancer Research.

[2]  Johan Staaf,et al.  Landscape of somatic allelic imbalances and copy number alterations in human lung carcinoma , 2013, International journal of cancer.

[3]  T. Betsuyaku,et al.  Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC , 2013, Molecular Cancer Research.

[4]  Michael Peyton,et al.  An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance , 2012, Clinical Cancer Research.

[5]  Mats Lambe,et al.  Biomarker Discovery in Non–Small Cell Lung Cancer: Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation , 2012, Clinical Cancer Research.

[6]  P. Validire,et al.  A Comparative and Integrative Approach Identifies ATPase Family, AAA Domain Containing 2 as a Likely Driver of Cell Proliferation in Lung Adenocarcinoma , 2012, Clinical Cancer Research.

[7]  Y. Bossé,et al.  Molecular signature of smoking in human lung tissues. , 2012, Cancer research.

[8]  S. Lam,et al.  Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression , 2012, Genome research.

[9]  A. Bashashati,et al.  Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer , 2012, Genome research.

[10]  Matthew D. Wilkerson,et al.  Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation , 2012, PloS one.

[11]  Yuki Togashi,et al.  RET, ROS1 and ALK fusions in lung cancer , 2012, Nature Medicine.

[12]  I. Wistuba,et al.  Pulmonary adenocarcinoma: A renewed entity in 2011 , 2012, Respirology.

[13]  Johan Staaf,et al.  Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer , 2011, Breast Cancer Research.

[14]  L. Holmberg,et al.  Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[15]  Jeremy J. W. Chen,et al.  Clustered genomic alterations in chromosome 7p dictate outcomes and targeted treatment responses of lung adenocarcinoma with EGFR-activating mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  J Downward,et al.  An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis , 2011, Oncogene.

[17]  Xihong Lin,et al.  Impact on Disease Development, Genomic Location and Biological Function of Copy Number Alterations in Non-Small Cell Lung Cancer , 2011, PloS one.

[18]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[19]  Philippe Broët,et al.  Genomic Profiles Specific to Patient Ethnicity in Lung Adenocarcinoma , 2011, Clinical Cancer Research.

[20]  David M. Thomas,et al.  Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer , 2011, BMC Cancer.

[21]  I. Petersen,et al.  Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer , 2010, Science Translational Medicine.

[22]  B. Job,et al.  Genomic Aberrations in Lung Adenocarcinoma in Never Smokers , 2010, PloS one.

[23]  William Pao,et al.  Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer , 2010, Nature Reviews Cancer.

[24]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[25]  Chuhsing Kate Hsiao,et al.  Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[26]  C. Tzeng,et al.  Chromosomal imbalances in lung adenocarcinomas with or without mutations in the epidermal growth factor receptor gene , 2010, Respirology.

[27]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[28]  B. Peters,et al.  Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. , 2009, Cancer cell.

[29]  E. Barillot,et al.  Genome Alteration Print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays , 2009, Genome Biology.

[30]  L. Heasley,et al.  The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. , 2009, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[31]  Keitaro Matsuo,et al.  Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[33]  Laura Tolosi,et al.  Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. , 2009, The Journal of clinical investigation.

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

[35]  Shingo Matsumoto,et al.  Whole genome comparison of allelic imbalance between noninvasive and invasive small-sized lung adenocarcinomas. , 2009, Cancer research.

[36]  E. C. Xu,et al.  Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients. , 2008, Lung cancer.

[37]  M. Ringnér,et al.  Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays , 2008, Genome Biology.

[38]  P. Laurent-Puig,et al.  Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma , 2008, BMC Medical Genomics.

[39]  S. Wacholder,et al.  Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival , 2008, PloS one.

[40]  J. Cigudosa,et al.  Expression signatures in lung cancer reveal a profile for EGFR‐mutant tumours and identify selective PIK3CA overexpression by gene amplification , 2008, The Journal of pathology.

[41]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[42]  P. Sebastiani,et al.  Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression , 2007, Genome Biology.

[43]  Ayumi Kasai,et al.  Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathway. , 2007, Cancer letters.

[44]  S. Hirohashi,et al.  Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma , 2007, Cancer science.

[45]  Stefano Monti,et al.  Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  Takayuki Kosaka,et al.  Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  G. Cavet,et al.  Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients , 2005, Clinical Cancer Research.

[48]  S. Hirohashi,et al.  Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features , 2005, Clinical Cancer Research.

[49]  M. Meyerson,et al.  Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. , 2005, Cancer research.

[50]  Elisabeth Brambilla,et al.  Pathology and genetics of tumours of the lung , pleura, thymus and heart , 2004 .

[51]  Daniel Jones.  Anticancer drugs: To the rescue? , 2004, Nature Reviews Drug Discovery.

[52]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[53]  Jonathan W. Pillow,et al.  POSTER PRESENTATION Open Access , 2013 .

[54]  S. Miyano,et al.  Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. , 2012, Cancer research.

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

[56]  J. Mesirov,et al.  An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis , 2005, Nature Genetics.

[57]  Cdm Fletcher,et al.  World Health Organization Classification of Tumours , 2002 .