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

Abstract

PurposeThe purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis.Patients and MethodsOne hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181).ResultsIGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis.ConclusionIGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

Expression and Clinical Significance of mTOR in Surgically Resected Non-small Cell Lung Cancer Tissues: a Case Control Study

“…In a retrospective study, Cappuzzo et al reported that 76.4% surgically resected NSCLC were positive IGF-1R expression (Cappuzzo et al, 2010). Dziadziuszko's group reported 84% NSCLC samples showed IGF-1R immunopositive staining (Dziadziuszko et al, 2010). They also demonstrated the high level IGF-1R expression was significantly associated with squamous cell histology and late stage.…”

Clinical significance of immunohistochemical expression of insulin-like growth factor-1 receptor and matrix metalloproteinase-7 in resected non-small cell lung cancer

“…Dziadziuszko et al (17) found that IGF-1R expression was higher in squamous cell carcinomas than in other histological types and was associated with disease stage. Cappuzzo et al (18) reported that a positive IGF-1R expression was significantly associated with squamous cell histology and grade III differentiation.…”

“…In stage I disease, high IGF-1R expression was associated with significantly shorter survival than low IGF-1R expression. Dziadziuszko et al (17) evaluated 189 NSCLCs and showed that the IGF-1R gene copy number is of prognostic value; nonetheless, IGF-1R protein expression upon immunohistochemical analysis was not related to survival. Ludovini et al (19) reported that IGF-1R protein expression alone was not significantly associated with survival, although high co-expression of both IGF-1R and epidermal growth factor receptor was associated with shorter Table IV.…”

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

“…Other studies on cancer have revealed that the lack of correlation between mRNA and protein levels can be attributed to mRNA translational silencing, cleavage, or alternative splicing (Dziadziuszko et al 2010, Mountzios et al 2013. In the IGF1R context, alternative mRNA splicing can lead to distinct protein degradation rates in cancer cells (Mountzios et al 2013) while the frequently expressed isoform (alpha) of IGF1R is not directly associated with global IGF1R gene expression (Pollak 2012).…”