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Grant Details

Grant Number: 5R01CA194189-06 Interpret this number
Primary Investigator: Wiemels, Joseph
Organization: University Of Southern California
Project Title: Genetic Susceptibility to Pediatric Glioma Inindividuals and Diverse Populations
Fiscal Year: 2020


Abstract

 DESCRIPTION (provided by applicant): Brain tumors are the most common solid tumor and the second most common malignancy in children. Nearly 2,000 pediatric gliomas (PG) are diagnosed annually in U.S. children under the age of 15, only half of whom survive into adulthood. 80% of survivors experience life-threatening conditions related to treatment, including stroke and second malignancies. Despite clear evidence of a genetic component underlying PG risk, little is known about heritable factors affecting this deadly brain tumor. As previously demonstrated for adult glioma, identification of robust and validated genetic risk factors can lead to improved risk stratification and reveal the biologic pathways fundamental to the disease pathogenesis. Previous studies seeking to identify genetic risk factors for PG were limited by small sample size. This obstacle rendered studies inadequate for the identification of authentic genetic associations in high-throughput fashion. Furthermore, technological limitations have forced prior studies to focus on common genetic variation, which may be only one component of the genetic origins underlying PG risk. The hypothesis that both rare and common genetic variation contribute to PG risk, and risk of specific subtypes, will be formally tested in this proposal. To achieve this, a population-based case-control study, nested within the California Birth Cohort (CBC), has been developed. Genome-wide analysis of common and rare genetic variants will be conducted using existing archived neonatal bloodspots from 2,920 Californian children diagnosed with PG between 1988 and 2013, and 1:1 matched controls. First, DNA from 300 children with malignant astrocytoma and 100 controls will undergo whole-exome sequencing (WES) to identify rare variants contributing to disease risk (Minor Allele Frequency<1%). Genes displaying significant enrichment of rare variants in affected children compared to CBC and public control exomes will be validated by targeted sequencing in an additional 675 malignant astrocytoma case children and 875 control children from the CBC. Next, 20,000 promising low-frequency variants (MAF 1-5%) identified from the WES will be added as custom content to a genome-wide genotyping array, already containing 818,000 common variants. DNA samples from all 2,920 CBC case children and 2,920 CBC control children will undergo genome-wide genotyping to perform an empirically-enriched genome-wide association study (eeGWAS). The eeGWAS analysis can identify both low-frequency and common variants underlying PG risk, and is statistically powered for both pooled and subtype-stratified analyses. Approximately 1,500 variants identified by the eeGWAS will undergo attempted replication in 1,210 case and 1,850 control children from three collaborating institutions. By leveraging the unique and mature resources within the Genetic Diseases Branch of the California Department of Public Health, this registry-based approach will yield an unprecedentedly large sample size. The identification of both rare and common variants underlying PG risk can expose new knowledge leading to improved care of children, adolescents, and young adults facing this diagnosis.



Publications

Birth characteristics and risk of Ewing sarcoma.
Authors: Wiemels J.L. , Wang R. , Feng Q. , Yee A.C. , Morimoto L.M. , Metayer C. , Ma X. .
Source: Cancer Causes & Control : Ccc, 2023-06-19 00:00:00.0; , .
EPub date: 2023-06-19 00:00:00.0.
PMID: 37335392
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Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
Authors: Foss-Skiftesvik J. , Li S. , Rosenbaum A. , Hagen C.M. , Stoltze U.K. , Ljungqvist S. , Hjalmars U. , Schmiegelow K. , Morimoto L. , de Smith A.J. , et al. .
Source: Neuro-oncology, 2023-02-22 00:00:00.0; , .
EPub date: 2023-02-22 00:00:00.0.
PMID: 36810956
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Influence of county-level geographic/ancestral origin on glioma incidence and outcomes in US Hispanics.
Authors: Walsh K.M. , Neff C. , Bondy M.L. , Kruchko C. , Huse J.T. , Amos C.I. , Barnholtz-Sloan J.S. , Ostrom Q.T. .
Source: Neuro-oncology, 2023-02-14 00:00:00.0; 25(2), p. 398-406.
PMID: 35868246
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Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children.
Authors: Li S. , Chiang C.W.K. , Myint S.S. , Arroyo K. , Chan T.F. , Morimoto L. , Metayer C. , de Smith A.J. , Walsh K.M. , Wiemels J.L. .
Source: Plos Genetics, 2022 Sep; 18(9), p. e1010388.
EPub date: 2022-09-07 00:00:00.0.
PMID: 36070312
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Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.
Authors: Li S. , Gai X. , Myint S.S. , Arroyo K. , Morimoto L. , Metayer C. , de Smith A.J. , Walsh K.M. , Wiemels J.L. .
Source: Neuro-oncology Advances, 2022 Jan-Dec; 4(1), p. vdac045.
EPub date: 2022-04-13 00:00:00.0.
PMID: 35571988
Related Citations

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.
Authors: Zhang C. , Ostrom Q.T. , Semmes E.C. , Ramaswamy V. , Hansen H.M. , Morimoto L. , de Smith A.J. , Pekmezci M. , Vaksman Z. , Hakonarson H. , et al. .
Source: Acta Neuropathologica Communications, 2020-10-28 00:00:00.0; 8(1), p. 173.
EPub date: 2020-10-28 00:00:00.0.
PMID: 33115534
Related Citations

Germline cancer predisposition variants and pediatric glioma: a population-based study in California.
Authors: Muskens I.S. , de Smith A.J. , Zhang C. , Hansen H.M. , Morimoto L. , Metayer C. , Ma X. , Walsh K.M. , Wiemels J.L. .
Source: Neuro-oncology, 2020-06-09 00:00:00.0; 22(6), p. 864-874.
PMID: 31970404
Related Citations

European genetic ancestry associated with risk of childhood ependymoma.
Authors: Zhang C. , Ostrom Q.T. , Hansen H.M. , Gonzalez-Maya J. , Hu D. , Ziv E. , Morimoto L. , de Smith A.J. , Muskens I.S. , Kline C.N. , et al. .
Source: Neuro-oncology, 2020-06-02 00:00:00.0; , .
EPub date: 2020-06-02 00:00:00.0.
PMID: 32607579
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Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population.
Authors: Zhang C. , Hansen H.M. , Semmes E.C. , Gonzalez-Maya J. , Morimoto L. , Wei Q. , Eward W.C. , DeWitt S.B. , Hurst J.H. , Metayer C. , et al. .
Source: Bone, 2020 Jan; 130, p. 115070.
EPub date: 2019-09-13 00:00:00.0.
PMID: 31525475
Related Citations

Germline genetic landscape of pediatric central nervous system tumors.
Authors: Muskens I.S. , Zhang C. , de Smith A.J. , Biegel J.A. , Walsh K.M. , Wiemels J.L. .
Source: Neuro-oncology, 2019-11-04 00:00:00.0; 21(11), p. 1376-1388.
PMID: 31247102
Related Citations

Risk factors for childhood and adult primary brain tumors.
Authors: Ostrom Q.T. , Adel Fahmideh M. , Cote D.J. , Muskens I.S. , Schraw J.M. , Scheurer M.E. , Bondy M.L. .
Source: Neuro-oncology, 2019-11-04 00:00:00.0; 21(11), p. 1357-1375.
PMID: 31301133
Related Citations

Genetic determinants of childhood and adult height associated with osteosarcoma risk.
Authors: Zhang C. , Morimoto L.M. , de Smith A.J. , Hansen H.M. , Gonzalez-Maya J. , Endicott A.A. , Smirnov I.V. , Metayer C. , Wei Q. , Eward W.C. , et al. .
Source: Cancer, 2018-10-12 00:00:00.0; , .
EPub date: 2018-10-12 00:00:00.0.
PMID: 30311632
Related Citations

Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.
Authors: Walsh K.M. , Whitehead T.P. , de Smith A.J. , Smirnov I.V. , Park M. , Endicott A.A. , Francis S.S. , Codd V. , ENGAGE Consortium Telomere Group , Samani N.J. , et al. .
Source: Carcinogenesis, 2016 06; 37(6), p. 576-82.
PMID: 27207662
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