Prevalence of pathogenic germline variants in adult-type diffuse glioma

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

doi:10.1093/nop/npad033

Prevalence of pathogenic germline variants in adult-type diffuse glioma

Neurooncol Pract. 2023 Jun 21;10(5):482-490. doi: 10.1093/nop/npad033. eCollection 2023 Oct.

Authors

Malcolm F McDonald^{1

2}, Lyndsey L Prather³, Cassandra R Helfer³, Ethan B Ludmir⁴, Alfredo E Echeverria⁵, Shlomit Yust-Katz⁶, Akash J Patel^{1

7

8}, Benjamin Deneen¹, Ganesh Rao¹, Ali Jalali¹, Shweta U Dhar^{9

10}, Chris I Amos⁹, Jacob J Mandel³

Affiliations

¹ Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA.
² Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
⁴ Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA.
⁵ Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas, USA.
⁶ Department of Neurology, Rabin Medical Center, Petah Tikva, Israel.
⁷ Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
⁸ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
¹⁰ Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.

PMID: 37720399
PMCID: PMC10502787 (available on 2024-06-21)
DOI: 10.1093/nop/npad033

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.

Keywords: diffuse glioma; glioblastoma; pathogenic germline variants.

© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.