Looking beyond year 1 in the molecular era of pediatric brain tumor diagnosis: confirmatory testing of germline variants found on tumor sequencing

Brittany L Greene; Shannon M Stasi; Michelle A Ting; Natalie Waligorski; Bonnie L Cole; Christina M Lockwood; Vera A Paulson; Jillian G Buchan; Amy Lee; Jeffrey G Ojemann; Richard G Ellenbogen; Jeffrey Stevens; Sarah E S Leary

doi:10.3389/fonc.2024.1338022

Looking beyond year 1 in the molecular era of pediatric brain tumor diagnosis: confirmatory testing of germline variants found on tumor sequencing

Front Oncol. 2024 Mar 6:14:1338022. doi: 10.3389/fonc.2024.1338022. eCollection 2024.

Authors

Brittany L Greene^{1

2

3}, Shannon M Stasi⁴, Michelle A Ting^{1

2

3}, Natalie Waligorski³, Bonnie L Cole^{4

5}, Christina M Lockwood⁵, Vera A Paulson⁵, Jillian G Buchan⁵, Amy Lee^{6

7}, Jeffrey G Ojemann^{6

7}, Richard G Ellenbogen^{6

7}, Jeffrey Stevens^{1

3}, Sarah E S Leary^{1

2

3}

Affiliations

¹ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, United States.
² Department of Pediatrics, University of Washington, Seattle, WA, United States.
³ Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA, United States.
⁴ Department of Laboratories, Seattle Children's Hospital, Seattle, WA, United States.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
⁶ Department of Pediatric Neurosurgery, Seattle Children's Hospital, Seattle, WA, United States.
⁷ Department of Neurological Surgery, University of Washington, Seattle, WA, United States.

Abstract

Purpose: Somatic molecular profiling of pediatric brain tumors aids with the diagnosis and treatment of patients with a variety of high- and low-grade central nervous system neoplasms. Here, we report follow-up targeted germline evaluation for patients with possible germline variants following tumor only testing in the initial year in which somatic molecular testing was implemented at a single institution.

Patients and methods: Somatic testing was completed for all tumors of the central nervous system (CNS) undergoing diagnostic workup at Seattle Children's Hospital during the study period of November 2015 to November 2016. Sequencing was performed in a College of American Pathologists-accredited, Clinical Laboratory Improvements Amendments-certified laboratory using UW-OncoPlex™ assay (version 5), a DNA-based targeted next generation sequencing panel validated to detect genetic alterations in 262 cancer-related genes. We tracked subsequent clinical evaluation and testing on a subgroup of this cohort found to have potential germline variants of interest.

Results: Molecular sequencing of 88 patients' tumors identified 31 patients with variants that warranted consideration of germline testing. To date, 19 (61%) patients have been tested. Testing confirmed germline variants for ten patients (31% of those identified for testing), one with two germline variants (NF1 and mosaic TP53). Eight (26%) patients died before germline testing was sent. One patient (13%) has not yet had testing.

Conclusion: Clinically validated molecular profiling of pediatric brain tumors identifies patients who warrant further germline evaluation. Despite this, only a subset of these patients underwent the indicated confirmatory sequencing. Further work is needed to identify barriers and facilitators to this testing, including the role of genetic counseling and consideration of upfront paired somatic-germline testing.

Keywords: brain tumor; childhood cancer; germline; molecular testing; next-generation sequencing.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Supported by the Seattle Children’s Hospital Funding Hope Award and the Pediatric Brain Tumor Research Fund. Also supported in part through the Focus on Kids Laboratory Guild and from a gift to Seattle Children’s Hospital from Kandace and Richard Holley. BG is supported in part by the Rally Foundation for Childhood Cancer Research.