We propose an international multi-center multidisciplinary study to identify susceptibility genes in high-risk familial brain tumor pedigrees using the most sophisticated genetic analysis methods available. This research team is uniquely positioned to characterize genetic risk of familial brain tumors, and conduct important translational research studies that will enhance our understanding into the etiology of brain tumors. We define familial brain tumors as those pedigrees in which two or more relatives have been diagnosed with a glioma that is not associated with known genetic syndromes. From research that we and others have conducted support several important observations that familial aggregation of brain tumors exists, and recent linkage analyses shows that there is strong suggestive evidence for susceptibility genes in 6 separate regions on chromosomes 1p, 1q, 8p, 9p, 10p, and 15q with LOD Scores ranging from 1.07 to 3.35. Based on these observations, we hypothesize that there are specific discoverable genotypes that increase the risk of developing brain tumors. We will study high-risk familial pedigrees using newly developed but proven gene mapping techniques. We propose the following specific aims:
Specific Aim 1 : Establish a cohort of 400 high-risk pedigrees for genetic linkage analysis. We will screen and obtain epidemiologic data from approximately 17,08 glioma cases to identify a target of 400 families. We will establish a cohort of the first and second-degree relatives from these glioma cases, to obtain new knowledge about how cancer aggregates in glioma families. A cohort of multiplex extended pedigrees will be created from the 400 glioma families for genetic analysis. We will also acquire biospecimens (blood and tumor tissue), and risk factor data from relevant family members. This will be the largest collection of glioma families that will provide us sufficient power to identify susceptibility genes and eventually identify functional mutations for this heterogenous disease.
Specific Aim 2 : Identify candidate regions linked to familial brain tumors. To strengthen evidence of linkage to regions found in our preliminary analysis, and to identify additional regions linked to brain tumors, we will genotype informative glioma pedigrees identified in aim 1 using Affymetrix 10K GeneChip with markers spaced throughout the genome, and conduct a genome-wide multipoint linkage scan with these markers. All regions with a lod score of 1.05 will be taken forward for further analysis.
Specific Aim 3 : Fine map regions established in Aim 2 by genotyping selected SNPs from genome databases. We will attempt to further refine the regions identified in Aim 2 to less than 1 cM by using approximately 1,500 - 2,000 carefully selected SNPs. The prioritization of regions will be based on a combination of the strength of evidence for linkage from families of various ethnic backgrounds and the presence of obvious candidate genes. Through such efforts, this study will identify susceptibility genes that will provide a better understanding of the mechanisms of brain tumor etiology. This information has translational significance for brain tumor patients and their families, and will enable us to develop appropriate genetic screening and counseling approaches to reduce the incidence and mortality of this disease.
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