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Germline cancer predisposition variants and pediatric glioma: a population-based study in California.

Publication ,  Journal Article
Muskens, IS; de Smith, AJ; Zhang, C; Hansen, HM; Morimoto, L; Metayer, C; Ma, X; Walsh, KM; Wiemels, JL
Published in: Neuro Oncol
June 9, 2020

BACKGROUND: Pediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level. METHODS: DNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes. RESULTS: We identified 33 putatively pathogenic germline variants among 31 patients (11.1%) which were located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N = 9/63). Five variants were located in tumor protein 53 (TP53), of which 4 were identified among patients with glioblastoma (6.3%, N = 4/63). The next most frequently mutated gene was neurofibromatosis 1 (NF1), in which putatively pathogenic variants were identified in 4 patients with astrocytoma not otherwise specified. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (odds ratio, 32.8, P = 8.04 × 10-7). CONCLUSION: A considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.

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Published In

Neuro Oncol

DOI

EISSN

1523-5866

Publication Date

June 9, 2020

Volume

22

Issue

6

Start / End Page

864 / 874

Location

England

Related Subject Headings

  • Oncology & Carcinogenesis
  • Humans
  • Glioma
  • Germ-Line Mutation
  • Genetic Predisposition to Disease
  • Child
  • California
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences
 

Citation

APA
Chicago
ICMJE
MLA
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Muskens, I. S., de Smith, A. J., Zhang, C., Hansen, H. M., Morimoto, L., Metayer, C., … Wiemels, J. L. (2020). Germline cancer predisposition variants and pediatric glioma: a population-based study in California. Neuro Oncol, 22(6), 864–874. https://doi.org/10.1093/neuonc/noaa014
Muskens, Ivo S., Adam J. de Smith, Chenan Zhang, Helen M. Hansen, Libby Morimoto, Catherine Metayer, Xiaomei Ma, Kyle M. Walsh, and Joseph L. Wiemels. “Germline cancer predisposition variants and pediatric glioma: a population-based study in California.Neuro Oncol 22, no. 6 (June 9, 2020): 864–74. https://doi.org/10.1093/neuonc/noaa014.
Muskens IS, de Smith AJ, Zhang C, Hansen HM, Morimoto L, Metayer C, et al. Germline cancer predisposition variants and pediatric glioma: a population-based study in California. Neuro Oncol. 2020 Jun 9;22(6):864–74.
Muskens, Ivo S., et al. “Germline cancer predisposition variants and pediatric glioma: a population-based study in California.Neuro Oncol, vol. 22, no. 6, June 2020, pp. 864–74. Pubmed, doi:10.1093/neuonc/noaa014.
Muskens IS, de Smith AJ, Zhang C, Hansen HM, Morimoto L, Metayer C, Ma X, Walsh KM, Wiemels JL. Germline cancer predisposition variants and pediatric glioma: a population-based study in California. Neuro Oncol. 2020 Jun 9;22(6):864–874.
Journal cover image

Published In

Neuro Oncol

DOI

EISSN

1523-5866

Publication Date

June 9, 2020

Volume

22

Issue

6

Start / End Page

864 / 874

Location

England

Related Subject Headings

  • Oncology & Carcinogenesis
  • Humans
  • Glioma
  • Germ-Line Mutation
  • Genetic Predisposition to Disease
  • Child
  • California
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences