title: Mutational analysis of the insulin-like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients.
abstract: The insulin-like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well-documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single-nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether theIGF1RTK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in theIGF1RTK domain (exons 16-21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease-free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in theIGF1RTK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to theEGFRTK domain, theIGF1RTK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland.
authors.forename: Kathy
authors.initials: K
authors.lastname: Gately
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland.
authors.forename: Lydia
authors.initials: L
authors.lastname: Forde
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gray
authors.affiliation: Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland.
authors.forename: Derek
authors.initials: D
authors.lastname: Morris
authors.affiliation: Discipline of Biochemistry, National University of Ireland, Galway, Republic of Ireland.
authors.forename: Aidan
authors.initials: A
authors.lastname: Corvin
authors.affiliation: Molecular Pathology Research Group, Trinity College, Coombe Womens and Infants University Hospital, Dublin, Republic of Ireland.
authors.forename: Prerna
authors.initials: P
authors.lastname: Tewari
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland ; Medical Oncology, Princess Alexandra Hospital, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
keywords: insulin-like growth factor 1 receptor; non-small cell lung cancer; single-nucleotide polymorphism; targeted therapy