The development of glioblastoma (GBM) has been hypothesized to be associated with relatively common germline alterations with limited penetrance. Recently, two genome-wide association studies (GWAS) using various single nucleotide polymorphism (SNP) array platforms have been performed in gliomas. Collaborating with the group at the University of California at San Francisco (UCSF) we recently reported that SNPs mapping near CDKN2A/B/ARF (9p21) and RTEL1 (20q13) are associated with the development of high grade astrocytomas. In a separate study of patients with gliomas, MD Anderson and European groups observed these associations as well as associations near TERT (5p15) and CCDC26/MLZE (8q24). A re-analysis of UCSF/Mayo data suggests that the RTEL1 (20q13), TERT (5p15) and CCDC26/MLZE (8q24) associations are largely restricted to patients with GBM, anaplastic astrocytoma and with oligodendroglioma, respectively - suggesting that different germline polymorphisms are associated with the development of different glioma subtypes. In this grant application we propose to further validate the germline alteration(s) within and/or near to the CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions that are associated with the development of glioma, to correlate alteration status with somatic genetic and expression alterations, with pathologic variables and with clinical parameters.
Our Specific Aims are:
Aim 1 : Perform detailed germline genetic analysis of the associated CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions using three cohorts of prospectively glioma cases and controls to estimate the prevalence and relative risk of known polymorphisms and new alterations.
Aim 2 : Evaluate the clinical, histopathologic, and molecular pathologic relevance of the germline CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) alterations. This application is designed to validate the alterations in each of the four regions associated with glioma development. Importantly, It will evaluate the clinical, pathologic and molecular pathologic relevance of these alterations.

Public Health Relevance

Gliomas cause significant morbidity and mortality. Approximately 18,500 people in the U.S. are diagnosed with glioma each year. Because most gliomas are biologically aggressive, approximately 12,800 people in the U.S. succumb to these tumors every year. Understanding the predisposition to gliomas will have major implications for the prevention of gliomas as well as the management of these tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Oi, N; Yuan, J; Malakhova, M et al. (2015) Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1. Oncogene 34:2660-71
Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N et al. (2014) Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells. Cancer Res 74:484-96
Bradley, Barrie S; Loftus, Joseph C; Mielke, Clinton J et al. (2014) Differential expression of microRNAs as predictors of glioblastoma phenotypes. BMC Bioinformatics 15:21
Walsh, Kyle M; Codd, Veryan; Smirnov, Ivan V et al. (2014) Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat Genet 46:731-5
Bell, Michael P; Renner, Danielle N; Johnson, Aaron J et al. (2014) An elite controller of picornavirus infection targets an epitope that is resistant to immune escape. PLoS One 9:e94332
Catteau, Aurélie; Girardi, Hélène; Monville, Florence et al. (2014) A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma. Acta Neuropathol Commun 2:58
Johnson, Holly L; Jin, Fang; Pirko, Istvan et al. (2014) Theiler's murine encephalomyelitis virus as an experimental model system to study the mechanism of blood-brain barrier disruption. J Neurovirol 20:107-12
Gupta, Shiv K; Mladek, Ann C; Carlson, Brett L et al. (2014) Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts. Clin Cancer Res 20:3730-41
Assefnia, Shahin; Dakshanamurthy, Sivanesan; Guidry Auvil, Jaime M et al. (2014) Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies. Oncotarget 5:1458-74
Wang, Enfeng; Zhang, Chunyang; Polavaram, Navatha et al. (2014) The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme. PLoS One 9:e86102

Showing the most recent 10 out of 103 publications