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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Pediatric Oncology
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1441958
This article is part of the Research Topic New Insights into Cancer Predisposition Syndromes in Pediatric Hematology-Oncology View all 5 articles

Frequency of pathogenic germline variants in pediatric medulloblastoma survivors

Provisionally accepted
D Matthew Gianferante D Matthew Gianferante 1,2*Donald Rees Donald Rees 1,2,3Jung Kim Jung Kim 1Theodora Stavrou Theodora Stavrou 4Gregory Reaman Gregory Reaman 5Yadav Sapkota Yadav Sapkota 6M. Monica Gramatges M. Monica Gramatges 7Lindsay M. Morton Lindsay M. Morton 1Melissa M. Hudson Melissa M. Hudson 6Gregory T. Armstrong Gregory T. Armstrong 6Neal D. Freedman Neal D. Freedman 1Wen-Yi Huang Wen-Yi Huang 1W. Ryan Diver W. Ryan Diver 8Adriana Lori Adriana Lori 8Wen Luo Wen Luo 9Belynda D. Hicks Belynda D. Hicks 9Jia Liu Jia Liu 9Amy A. Hutchinson Amy A. Hutchinson 9Alisa M. Goldstein Alisa M. Goldstein 1Lisa Mirabello Lisa Mirabello 1
  • 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute (NIH), Bethesda, United States
  • 2 Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States
  • 3 Walter Reed National Military Medical Center, Bethesda, Maryland, United States
  • 4 Ministry of Health (Greece), Athens, Greece
  • 5 Division of Cancer Treatment and Diagnosis, National Cancer Institute (NIH), Bethesda, Maryland, United States
  • 6 Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
  • 7 Division of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
  • 8 Department of Population Science, American Cancer Society, Atlanta, Georgia, United States
  • 9 Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick (NIH), Frederick, Maryland, United States

The final, formatted version of the article will be published soon.

    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 ).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.

    Keywords: Pathogenic, germline, pediatric, Medulloblastoma, Survivor

    Received: 31 May 2024; Accepted: 17 Jul 2024.

    Copyright: © 2024 Gianferante, Rees, Kim, Stavrou, Reaman, Sapkota, Gramatges, Morton, Hudson, Armstrong, Freedman, Huang, Diver, Lori, Luo, Hicks, Liu, Hutchinson, Goldstein and Mirabello. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: D Matthew Gianferante, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NIH), Bethesda, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.