The 3′ UTR IGF2R-A2/B2 variant is associated with increased tumor growth and advanced stages in non-small cell lung cancer

Normal function of Insulin-like Growth Factor II Receptor (IGF2R) gene has been associated with negative control of tumor growth in vivo and in vitro. Rare alleles at a 3′ UTR short tandem repeat polymorphism of IGF2R are known to decrease transcript stability. One such allele (A2/B2) increases significantly the risk of oral squamous cell carcinoma and non-small cell lung carcinoma (NSCLC) in Caucasians. To determine potential association(s) between A2/B2 presence and development and/or progression of disease, we examined in 103 NSCLC patients, free of IGF2R allelic imbalance aberrations, the 3′ UTR allelic status in relation to tumor kinetic parameters (proliferation index-PI and apoptotic index-AI) and clinicopathological data. PCR and automated sequence analyses were employed to genotype the IGF2R 3′ UTR polymorphism. Given that, oncogenic mitogens, which escape degradation by IGF2R, can also activate p53 through a DNA damage response, the patterns between p53 status and IGF2R genetic constitution were also evaluated in relation to the above parameters. The A2/B2 variant was significantly more common (p = 0.005, χ2-test) in lung cancer patients (25% vs 15%). Its presence was accompanied by high cellular proliferation (p = 0.028, t-test) along with increased tumor cell growth (GI = PI/AI) (p = 0.022, t-test) and it was significantly found in advanced stages. Also, patients carrying the A2/B2 in their genetic constitution that exhibit aberrant p53 expression have faster growing tumors and progress more rapidly to advanced stages. In conclusion, the IGF2R-A2/B2 variant probably provides a selective advantage for NSCLC progression through increased tumor growth.