Insulin-like growth factor 1 pathway mutations and protein expression in resected non-small cell lung cancer.

The purpose of this study was to characterize the prevalence of insulin-like growth factor 1 receptor (IGF1R) mutations, single nucleotide polymorphisms (SNP), and protein overexpression in surgically resected non-small cell lung cancers in relation to patient characteristics and prognosis. This retrospective study was conducted on 304 patients with non-small cell lung cancers who underwent curative pulmonary resection (median follow-up for surviving patients, 3.6 years). IGF1R gene alterations (n = 304) and protein expression (n = 181) were evaluated by polymerase chain reaction-based assays and immunohistochemistry, respectively. Membranous and cytoplasmic staining were analyzed separately. In an exploratory analysis, 1 silent mutation in exon 16 and 3 mutations in introns of the IGF1R gene comprising the tyrosine kinase domain were detected. Moreover, evaluating selected IGF1R SNPs, patients with adenocarcinomas and homozygous for the rs8038415 T-allele had a significantly better survival (P = .025) but no different disease-free survival. Regarding expression, membranous but not cytoplasmic IGF1R staining was higher in squamous cell carcinomas versus other histologies (P < .0001) and showed a trend to longer survival (P = .08). No association between SNP variations and protein expression was found. Membranous IGF1R protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis. SNPs and mutations can be detected and may harbor prognostic value. These alterations may be of interest when evaluating the IGF1R as potential therapeutic target and should receive further research.

[1]  S. Novello,et al.  Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  F. Cappuzzo,et al.  Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  P. Brodt,et al.  Enhanced invasion and liver colonization by lung carcinoma cells overexpressing the type 1 insulin-like growth factor receptor. , 1998, Experimental cell research.

[4]  F. Couch,et al.  Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[5]  L. Tanoue,et al.  Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma , 2010 .

[6]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[7]  T. Mok,et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. , 2009, The New England journal of medicine.

[8]  A. Casson,et al.  Insulin‐like growth factor type I receptor gene expression and obesity in esophageal adenocarcinoma , 2009, Molecular carcinogenesis.

[9]  H. Lenz,et al.  Germline Polymorphisms in Genes Involved in the IGF1 Pathway Predict Efficacy of Cetuximab in Wild-type KRAS mCRC Patients , 2010, Clinical Cancer Research.

[10]  J. A. Bishop,et al.  A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. , 2001, Human molecular genetics.

[11]  L. Crinò,et al.  High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  Michael Thomas,et al.  A comprehensive study of polymorphisms in ABCB1, ABCC2 and ABCG2 and lung cancer chemotherapy response and prognosis , 2012, International journal of cancer.

[13]  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.

[14]  H. Senn,et al.  Insulin-like growth factors and cancer. , 2002, The Lancet. Oncology.

[15]  V. Gismondi,et al.  A silent mutation in exon 14 of theAPC gene is associated with exon skipping in a FAP family , 2001, Journal of medical genetics.

[16]  S. Lippman,et al.  Akt/mTOR Counteract the Antitumor Activities of Cixutumumab, an Anti-Insulin–like Growth Factor I Receptor Monoclonal Antibody , 2011, Molecular Cancer Therapeutics.

[17]  Christoph Plass,et al.  Epigenetic screen identifies genotype- specific promoter DNA methylation and oncogenic potential of CHRNB4 , 2012, Oncogene.

[18]  E. Felip,et al.  Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. , 2012, The Lancet. Oncology.

[19]  Thomas L. Madden,et al.  BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences. , 1999, FEMS microbiology letters.

[20]  C. Korch,et al.  Development of an Integrated Genomic Classifier for a Novel Agent in Colorectal Cancer: Approach to Individualized Therapy in Early Development , 2010, Clinical Cancer Research.

[21]  A. Casson,et al.  A polymorphic variant of the insulin-like growth factor type I receptor gene modifies risk of obesity for esophageal adenocarcinoma. , 2009, Cancer epidemiology.

[22]  L. Ellis,et al.  Blockade of insulin-like growth factor I receptor function inhibits growth and angiogenesis of colon cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  H. Dienemann,et al.  Expression and mutational status of PDGFR in thymic tumours. , 2009, Anticancer research.

[24]  G. Sauter,et al.  Insulin‐like growth factor‐1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus , 2010, International journal of cancer.

[25]  K. Hess,et al.  Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer. , 2010, Gastroenterology.

[26]  David Sidransky,et al.  Emerging molecular markers of cancer , 2002, Nature Reviews Cancer.

[27]  F. Hirsch,et al.  Insulin-like growth factor receptor 1 (IGF1R) gene copy number is associated with survival in operable non-small-cell lung cancer: a comparison between IGF1R fluorescent in situ hybridization, protein expression, and mRNA expression. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  J. Mandell,et al.  Phosphorylation state-specific antibodies: applications in investigative and diagnostic pathology. , 2003, The American journal of pathology.