AUTHOR=Rees Donald , Gianferante D. Matthew , Kim Jung , Stavrou Theodora , Reaman Gregory , Sapkota Yadav , Gramatges M. Monica , Morton Lindsay M. , Hudson Melissa M. , Armstrong Gregory T. , Freedman Neal D. , Huang Wen-Yi , Diver W. Ryan , Lori Adriana , Luo Wen , Hicks Belynda D. , Liu Jia , Hutchinson Amy A. , Goldstein Alisa M. , Mirabello Lisa 

TITLE=Frequency of pathogenic germline variants in pediatric medulloblastoma survivors

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1441958

DOI=10.3389/fonc.2024.1441958

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in <italic>APC</italic>, <italic>ELP1</italic>, <italic>GPR161</italic>, <italic>PTCH1</italic>, <italic>SUFU</italic>, and <italic>TP53</italic> 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.</p></sec><sec><title>Methods</title><p>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 (<italic>APC</italic>, <italic>ELP1</italic>, <italic>GPR161</italic>, <italic>PTCH1</italic>, <italic>SUFU</italic>, <italic>TP53)</italic> 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.</p></sec><sec><title>Results</title><p>Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10<sup>-3</sup>), 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<sup>-8</sup>). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were <italic>ELP1 (</italic>p=3.0x10<sup>-4</sup>) and <italic>SUFU</italic> (p=1.4x10<sup>-3</sup>).</p></sec><sec><title>Conclusion</title><p>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.</p></sec>