|Grant Number:||7R01CA139020-03 Interpret this number|
|Primary Investigator:||Bondy, Melissa|
|Organization:||Baylor College Of Medicine|
|Project Title:||International Case Control Study of Malignant Glioma|
DESCRIPTION (provided by applicant): Glioma comprises about 40% of all primary brain tumors accounting for as many as 26,000 U.S. and European deaths annually. Inherited susceptibility plays a role with 2-fold increased risk of glioma among first-degree relatives of glioma cases. We initiated a multi-center, international linkage study: "Genetic Epidemiology of Glioma International Consortium" in 2007 to address the role of inherited susceptibility. Since this study does not allow us currently to address the role of genetic susceptibility in sporadic cases, we propose this case- control study to address this gap. Members of the consortium have conducted genome wide association studies (GWAS) that will be the discovery phase (phase I). While of high value for discovery, we propose to recruit 6,000 newly diagnosed glioma cases and 6,000 age-gender-ethnicity-matched controls, and collect detailed epidemiologic data and biologic samples from the 13 participating Gliogene sites. We hypothesize that novel inherited variation influencing the susceptibility to glioma can be identified by high density SNP analysis, and propose the following specific aims: SA1: Identify common genetic variants contributing to the risk of glioma. We plan to conduct phases 2 and 3 of the 3 phase approach, specifically we will: (SA1a) Validate GWAS findings from the discovery sets, and replicate the top hits (~23,000 SNPs) with lowest p- values from the two phase GWA studies in a series of 2,000 cases and 2,000 controls (phase 2, validation). Validate the top hits from the test set (aim 1a). From stage 2, genes with SNPs displaying an association at pd10-4 (including the complete haplotype tagging - approximately 100 SNPs) will then be genotyped in a further series of 4,000 cases and 4,000 controls (stage 3, validation). SNPs significant at 10-7 or better will be considered in the final analyses. (SA1b). Using an a priori hypothesis that DNA repair in inflammation contribute to glioma risk, we will selectively interrogate DNA repair and inflammation pathway genes using data for select genes derived from the high-density array. We will conduct a hypothesis driven genetic association in DNA repair and in inflammation/immune function related genes with glioma risk using functional genomic and bioinformatic tools to interrogate available databases. (SA2): Evaluate gene-gene (G-G) and gene- environmental (G-E) interactions with strong biologic relevance to identify G-G and G-E interactions for glioma risk using machine-learning tools (MDR, FITF, and CART) in these exploratory analyses. There are no existing glioma case-control studies with sufficient numbers of biological samples and common epidemiologic data to conduct a comprehensive validation and replication study, or to address the issues of tumor heterogeneity as we will in this study. PUBLIC HEALTH RELEVANCE: Gliomas are a rare and understudied disease that is rapidly fatal. The proposed case-control study of primary malignant glioma (Gliogene Consortium) includes 13-centers, and will address the role of genetic susceptibility in sporadic cases. It will identify common genetic variants contributing to the risk of glioma from a genome wide association study.
Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors.
Authors: Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, Sarkar G, Caron AA, Kollmeyer TM, Praska CE, Chada AR, Halder C, Hansen HM, McCoy LS, Bracci PM, Marshall R, Zheng S, Reis GF, Pico AR, O'Neill BP, Buckner JC, Giannini C, Huse JT, Perry A, Tihan T, Berger MS, Chang SM, Prados MD, Wiemels J, Wiencke JK, Wrensch MR, Jenkins RB
Source: N Engl J Med, 2015 Jun 25;372(26), p. 2499-508.
EPub date: 2015 Jun 10.
Genetic Modulation of Neurocognitive Function in Glioma Patients.
Authors: Liu Y, Zhou R, Sulman EP, Scheurer ME, Boehling N, Armstrong GN, Tsavachidis S, Liang FW, Etzel CJ, Conrad CA, Gilbert MR, Armstrong TS, Bondy ML, Wefel JS
Source: Clin Cancer Res, 2015 Apr 22;null, p. null.
EPub date: 2015 Apr 22.
CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas.
Authors: Reis GF, Pekmezci M, Hansen HM, Rice T, Marshall RE, Molinaro AM, Phillips JJ, Vogel H, Wiencke JK, Wrensch MR, Walsh KM, Perry A
Source: J Neuropathol Exp Neurol, 2015 May;74(5), p. 442-52.
A comparison of DNA methylation specific droplet digital PCR (ddPCR) and real time qPCR with flow cytometry in characterizing human T cells in peripheral blood.
Authors: Wiencke JK, Bracci PM, Hsuang G, Zheng S, Hansen H, Wrensch MR, Rice T, Eliot M, Kelsey KT
Source: Epigenetics, 2014 Oct;9(10), p. 1360-5.
Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.
Authors: Walsh KM, Codd V, Smirnov IV, Rice T, Decker PA, Hansen HM, Kollmeyer T, Kosel ML, Molinaro AM, McCoy LS, Bracci PM, Cabriga BS, Pekmezci M, Zheng S, Wiemels JL, Pico AR, Tihan T, Berger MS, Chang SM, Prados MD, Lachance DH, O'Neill BP, Sicotte H, Eckel-Passow JE, ENGAGE Consortium Telomere Group, van der Harst P, Wiencke JK, Samani NJ, Jenkins RB, Wrensch MR
Source: Nat Genet, 2014 Jul;46(7), p. 731-5.
EPub date: 2014 Jun 8.
Exploring the association between melanoma and glioma risks.
Authors: Scarbrough PM, Akushevich I, Wrensch M, Il'yasova D
Source: Ann Epidemiol, 2014 Jun;24(6), p. 469-74.
EPub date: 2014 Mar 4.
Genome-wide methylation analyses in glioblastoma multiforme.
Authors: Lai RK, Chen Y, Guan X, Nousome D, Sharma C, Canoll P, Bruce J, Sloan AE, Cortes E, Vonsattel JP, Su T, Delgado-Cruzata L, Gurvich I, Santella RM, Ostrom Q, Lee A, Gregersen P, Barnholtz-Sloan J
Source: PLoS One, 2014;9(2), p. e89376.
EPub date: 2014 Feb 21.
HMG CoA reductase inhibitors, NSAIDs and risk of glioma.
Authors: Ferris JS, McCoy L, Neugut AI, Wrensch M, Lai R
Source: Int J Cancer, 2012 Sep 15;131(6), p. E1031-7.
EPub date: 2012 Apr 4.
Genetic advances in glioma: susceptibility genes and networks.
Authors: Liu Y, Shete S, Hosking F, Robertson L, Houlston R, Bondy M
Source: Curr Opin Genet Dev, 2010 Jun;20(3), p. 239-44.
EPub date: 2010 Mar 6.