Abstract 874: Genetic variation in the NOTCH stem cell signaling network in relation to risk of adult-onset glioma

Abstract

Abstract The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that plays a fundamental role during cell-fate specification in the developing mammalian nervous system. Mounting evidence suggest that this signaling network plays a critical oncogenic role in the development and progression of glioma. Stem-like cells in brain tumors require Notch for their survival and growth. Moreover, Notch-1 and its ligands, Delta-like-1 and Jagged-1 are overexpressed in both glioma cell lines and primary human gliomas. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. Finally, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in experimental models of brain tumors. In the present study, we tested whether single nucleotide polymorphisms (SNPs) in the genes encoding Notch-1 (NOTCH1 at 9q34) and its ligands, Delta-like-1 (DLL1 at 6q27) and Jagged-1 (JAG1 at 20p12-p11) are associated with the risk of glioma onset in a clinic-based case-control study conducted at medical centers in the southeastern US. A total of 29 candidate and haplotype tagging SNPs (10 SNPs in NOTCH1; 2 in DLL1 and 17 in JAG1) were genotyped using the Illumina Goldengate assay in 563 newly diagnosed (eg. nonrecurrent) 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 tumor. DNA was isolated from saliva samples. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs adjusting for age and gender. No consistent associations were observed for either examined variant in DLL1. An intronic SNP (rs3013300) in NOTCH1 located 9.2kb from the start codon was associated with an increased risk of astrocytomas (per variant “T” allele OR: 1.48; 95% CI: 1.12-1.96; p=0.006; MAF: 0.31), though not other glioma subtypes. Another intronic SNP in NOTCH1 (rs11574903) in weak linkage with the rs3013300 variant (r2: 0.10) was significantly associated with risk of oligodendrogliomas (per variant ‘T” allele OR: 1.68; 95% CI: 1.18-2.40; p=0.004; MAF: 0.22). This SNP is located 62bp downstream of a nonsynonymous SNP (rs115563691; V1671I) in NOTCH1. A SNP in the 3’UTR of the NOTCH1 ligand, JAG1 (rs8708), located in a putative micro-RNA binding site, was significantly associated with the risk of GBM (per variant “A” allele OR: 1.30; 95% CI: 1.06-1.59; p=0.010; MAF: 0.45). To our knowledge, this is the first study implicating genetic variants in the Notch stem cell signaling network with cancer risk. Further research is needed to confirm these findings and to elucidate putative causal variants in this pathway. 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 874. doi:10.1158/1538-7445.AM2011-874