Abstract 875: Genetic variation in the natural killer cell activating receptor NKG2D and its ligands in relation to glioma risk and outcome

Abstract

Natural killer (NK) cells play a key role in the immune response to certain infections and neoplasms. A major activating receptor of NK lymphocytes is NKG2D. In cancer, NKG2D ligands on transformed cells transmit danger signals to NKG2D-activated NK T cells culminating in cytolysis of malignant cells. A role for NK host defense in glioma is suggested by the expression of NKG2D ligands on glioma cells though not normal brain and correlation of NKG2D ligand expression with increasing WHO grade of malignancy. Genetic variation in NKG2D and its ligands has been associated with susceptibility to cancer and autoimmune diseases. We examined single nucleotide polymorphisms (SNPs) in genes affecting NK cell-mediated immune response for association with glioma risk and outcome in a case-control study encompassing 563 newly diagnosed glioma cases (including 324 WHO grade IV glioblastomas (GBM); 145 WHO grade II or III astrocytomas and 94 oligoastrocytomas and oligodendrogliomas) and 629 healthy controls with no history of brain cancer. DNA was isolated from saliva samples. A total of 24 candidate SNPs were genotyped using the Illumina Goldengate assay in critical genes linked to NK immunosurveillance including KLRK1 (encoding NKG2D), key NKG2D ligands (MICA, MICB and RAET1E), and genes linked to tumor immunoresistance (IDO1, IDO2). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for glioma risk in relation to individual SNPs adjusting for age and gender. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for GBM-related death (203 deaths; median follow up: 11.2 months) for each examined SNP. A haplotype associated with low NK activity in peripheral lymphocytes, identified by SNPs in the NK complex gene region on 12p13-p12 and marked by rs1049174 in the 3’UTR of KLRK1 (minor allele frequency (MAF) in controls: 26%), was associated with an increased glioma risk (per variant “C” allele OR: 1.22; 95% CI: 1.02-1.46; p=0.030); associations with this SNP were most prominent among oligodendroglioma patients (per allele OR: 1.69; 95% CI: 1.20-2.38; p=0.0027). A putatively functional nonsynonymous SNP in MICA (rs1051794; Lys196Glu; MAF: 27%) had a borderline association with risk for GBM (per variant “A” allele OR: 1.24; 95% CI: 1.00-1.53; p=0.048) though not other glioma subtypes; the variant rs1051794 allele was associated with increased GBM mortality (per allele HR: 1.31; 95% CI: 1.04-1.65; p=0.020). An intronic SNP in IDO2 (rs2543072) associated with risk of astrocytic tumors (per variant “T” allele OR: 1.65; 95% CI: 1.19-2.30; p=0.003; MAF: 21%) was also associated with GBM mortality (per allele HR: 1.28; 95% CI: 1.00-1.62; p=0.046). These results provide evidence that genetic variation in NK immunosurveillance influences glioma susceptibility and may contribute to GBM aggressiveness.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 875. doi:10.1158/1538-7445.AM2011-875