Clustered genomic alterations in chromosome 7p dictate outcomes and targeted treatment responses of lung adenocarcinoma with EGFR-activating mutations.

PURPOSE Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. PATIENTS AND METHODS We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. RESULTS We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. CONCLUSION Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.

[1]  J. Shih,et al.  Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. , 2011, American journal of respiratory and critical care medicine.

[2]  M. Paquet,et al.  Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma. , 2011, Blood.

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

[4]  A. Gemma,et al.  F1000 highlights , 2010 .

[5]  G. Gores,et al.  GLI3-dependent repression of DR4 mediates hedgehog antagonism of TRAIL-induced apoptosis , 2010, Oncogene.

[6]  S. Toyooka,et al.  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. , 2010, The Lancet. Oncology.

[7]  J. Abbruzzese,et al.  F1000 highlights , 2009, JAMA.

[8]  R. McLendon,et al.  Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress. , 2009, Cancer research.

[9]  C. Moskaluk,et al.  Combined genomic and gene expression microarray profiling identifies ECOP as an upregulated gene in squamous cell carcinomas independent of DNA amplification , 2009, Oncogene.

[10]  M. Meyerson,et al.  PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. , 2009, Cancer research.

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

[12]  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.

[13]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

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

[15]  Yih-Leong Chang,et al.  Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Mutations Is Associated with Poor Gefitinib Treatment Response , 2008, Clinical Cancer Research.

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

[17]  Jude Kendall,et al.  Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer , 2007, Proceedings of the National Academy of Sciences.

[18]  Matthew Meyerson,et al.  Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. , 2007, Cancer cell.

[19]  H. Sasaki,et al.  PIK3CA mutation status in Japanese lung cancer patients. , 2006, Lung cancer.

[20]  M. Maemondo,et al.  Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  P. Jänne,et al.  Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Domain Mutations on the Outcome of Patients with Non–Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors , 2006, Clinical Cancer Research.

[22]  J. Minna,et al.  Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. , 2006, Journal of the National Cancer Institute.

[23]  Yih-Leong Chang,et al.  Epidermal growth factor receptor mutations in needle biopsy/aspiration samples predict response to gefitinib therapy and survival of patients with advanced nonsmall cell lung cancer , 2006, International journal of cancer.

[24]  S. Ramalingam,et al.  Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  Shih-Feng Tsai,et al.  High Frequency of Epidermal Growth Factor Receptor Mutations with Complex Patterns in Non–Small Cell Lung Cancers Related to Gefitinib Responsiveness in Taiwan , 2004, Clinical Cancer Research.

[26]  Takayuki Kosaka,et al.  Mutations of the Epidermal Growth Factor Receptor Gene in Lung Cancer , 2004, Cancer Research.

[27]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Daniel A. Haber,et al.  Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways , 2004, Science.

[29]  J. Rigas,et al.  Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[31]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[32]  M. Kuwano,et al.  Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. , 2004, Molecular cancer therapeutics.

[33]  David Cella,et al.  Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. , 2003, JAMA.

[34]  Masahiro Fukuoka,et al.  Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  C. James,et al.  Lanthionine synthetase components C-like 2 increases cellular sensitivity to adriamycin by decreasing the expression of P-glycoprotein through a transcription-mediated mechanism. , 2003, Cancer research.

[36]  F. Bray,et al.  Cancer burden in the year 2000. The global picture. , 2001, European journal of cancer.

[37]  Christian Klämbt,et al.  Epidermal growth factor receptor signaling , 2001, Current Biology.

[38]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[39]  S. Manoir,et al.  Comparative genomic hybridization analysis detects frequent, often high-level, overrepresentation of DNA sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas. , 1997, Cancer research.

[40]  M. Esteller Molecular Origins of Cancer Epigenetics in Cancer , 2022 .