Frequency of pathogenic germline variants in pediatric medulloblastoma survivors

Background Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC , ELP1 , GPR161 , PTCH1 , SUFU , and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions. Methods Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes ( APC , ELP1 , GPR161 , PTCH1 , SUFU , TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls. Results Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10 -3 ), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10 -8 ). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 ( p=3.0x10 -4 ) and SUFU (p=1.4x10 -3 ). Conclusion Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

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Publication Details

Journal
Frontiers in Oncology
Published
2024-08-09
DOI
https://doi.org/10.3389/fonc.2024.1441958
Citations
2
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.88

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article

Frequency of pathogenic germline variants in pediatric medulloblastoma survivors

Lindsay McOmber Morton, Gregory H. Reaman, Wen Luo, Lisa Mirabello et al.
2 citations
Frontiers in Oncology
Glioma Diagnosis and Treatment
0.88
article

Frequency of pathogenic germline variants in pediatric medulloblastoma survivors

Lindsay McOmber Morton, Gregory H. Reaman, Wen Luo, Lisa Mirabello, Yadav Sapkota, Maria Monica Gramatges, Adriana Lori, Alisa M. Goldstein, Gregory T. Armstrong, Belynda D. Hicks, W. Ryan Diver, Theodora Stavrou, Amy Hutchinson, Melissa M. Hudson, Neal D. Freedman, Jia Liu, Jung Kim, D. Matthew Gianferante, Wen‐Yi Huang, Donald Rees
article en
2 citations

Abstract

Background Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC , ELP1 , GPR161 , PTCH1 , SUFU , and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions. Methods Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes ( APC , ELP1 , GPR161 , PTCH1 , SUFU , TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls. Results Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10 -3 ), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10 -8 ). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 ( p=3.0x10 -4 ) and SUFU (p=1.4x10 -3 ). Conclusion Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

Frontiers in OncologyVol. 14
American Cancer Society (US), National Institutes of Health (US), St. Jude Children's Research Hospital (US), Uniformed Services University of the Health Sciences (US), Baylor College of Medicine (US), Walter Reed National Military Medical Center (US), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Texas Children's Hospital (US), Ministry of Health (GR)
Centers for Disease Control and Prevention, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 25%
Glioma Diagnosis and Treatment
0.88
DOIOpen Access PDFOpenAlex
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