Prevalence of Pathogenic Germline Variants in Adult-Type Diffuse Glioma

Authors

Malcolm F McDonald
Lyndsey L Prather
Cassandra R Helfer
Ethan B Ludmir
Alfredo E Echeverria
Shlomit Yust-Katz
Akash J Patel
Benjamin Deneen
Ganesh Rao
Ali Jalali
Shweta U Dhar
Chris I Amos
Jacob J Mandel

Publication Date

10-1-2023

Journal

Neuro-Oncology Practice

DOI

10.1093/nop/npad033

PMID

37720399

PMCID

PMC10502787

PubMedCentral® Posted Date

6-21-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

diffuse glioma, glioblastoma, pathogenic germline variants

Abstract

BACKGROUND: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma.

METHODS: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected.

RESULTS: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH, and CHEK2 were most common (3/15, 20% each). BRCA1 variants occurred in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Prior cancer diagnosis was found in 5/15 patients (33%). Second-hit somatic variants were seen in 3/15 patients (20%) in NF1, MUTYH, and MSH2. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. 14/15 (93%) of patients discovered their pathogenic variant as a result of their paired glioma sequencing.

CONCLUSIONS: These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further studies that can determine the role of variants in gliomagenesis and confirm the occurrence and types of pathogenic germline variants in patients with IDH wild type compared to IDH mutant tumors are necessary.