Subclonal Cancer Driver Mutations Are Prevalent in the Unresected Peritumoral Edema of Adult Diffuse Gliomas

Q: What problem does the study address in sequencing peritumoral edema mutations?

The study addresses the inability to distinguish next-generation sequencing noise from true, weak tumor mutation signals present within peritumoral edema.

Q: What is True2, and what performance does it achieve?

True2 is a sequencing workflow that reduces NGS-associated errors to less than 1 false positive per 100 kb panel positions while detecting 97.6% of somatic mutations with allele frequency ≥0.1%.

Q: What molecular relationship does surgery show between bulk tumors and peritumoral edema?

The tumor and peritumoral edema show similar mutation burden, indicating surgery can debulk cancers physically but not molecularly.

Sep 21, 2026

Uploaded by Lucas Martin

Adult diffuse gliomas commonly recur regardless of therapy, with recurrence often arising from peritumoral edema adjacent to the resected bulk tumor. Profiling somatic mutations in infiltrative malignant cells within this unresected region could clarify residual disease. A key challenge is separating true weak tumor signals from next-generation sequencing noise. True2 reduces sequencing errors to <1 false positive per 100 kb while detecting mutations at allele frequencies ≥0.1%.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Significance

Introduction

Background on adult diffuse gliomas

Prior work and knowledge gaps

Subclonal Cancer Driver Mutations Are Prevalent in the Unresected Peritumoral Edema of Adult Diffuse Gliomas Hunter R. Underhill1,2,3, Michael Karsy4, Christian J. Davidson5, Sabine Hellwig6, Samuel Stevenson1, Eric A. Goold5, Sydney Vincenti7, Drew L. Sellers8, Charlie Dean3, Brion E. Harrison1, Mary P. Bronner3,5, Howard Colman3,4,9, and Randy L. Jensen3,4 ABSTRACT ◥ Adult diffuse gliomas commonly recur regardless of therapy. As recurrence typically arises from the peritumoral edema adjacent to the resected bulk tumor, the proﬁling of somatic mutations from inﬁltrative malignant cells within this critical, unresected region could provide important insights into residual disease. A key obstacle has been the inability to distinguish between nextgeneration sequencing (NGS) noise and the true but weak signal from tumor cells hidden among thenoncancerous brain tissue ofthe peritumoral edema. Here, we developed and validated True2 sequencing to reduce NGS-associated errors to < 1 false positive/100 kb panel positions while detecting 97.6% of somatic mutations with an allele frequency ≥0.1% . True2 was then used to study the tumor and peritumoral edema of 22 adult diffuse gliomas including glioblastoma, astrocytoma, oligodendroglioma, and NF1-related low-grade neuroglioma. The tumor and peritumoral edema displayed a similar mutation burden, indicating that surgery debulks these cancers physically but not molecularly. Moreover, variants in the peritumoral edema included unique cancer driver mutations absent in the bulk tumor. Finally, analysis of multiple samples from each patient revealed multiple subclones with unique mutations in the same gene in 17 of 22 patients, supporting the occurrence of convergent evolution in response to patient-speciﬁc selective pressures in the tumor microenvironment that may form the molecular foundation of recurrent disease. Collectively, True2 enables the detection of ultralow frequency mutations during molecular analyses of adult diffuse gliomas, which is necessary to understand cancer evolution, recurrence, and individual response to therapy. Signiﬁcance: True2 is a next-generation sequencing workﬂow that facilitates unbiased discovery of somatic mutations across the full range of variant allele frequencies, which could help identify residual disease vulnerabilities for targeted adjuvant therapies. Introduction Adult diffuse gliomas are a group of malignant, inﬁltrative tumors intrinsic to the central nervous system that arise from glial cells such as astrocytes and oligodendrocytes (1) . The World Health Organization (WHO) Classiﬁcation of Tumors of the Central Nervous System partitions adult diffuse gliomas into three types: (i) WHO grade 4 glioblastoma, isocitrate dehydrogenase (IDH)-wildtype, (ii) WHO grade 2–4 astrocytoma, IDH-mutant, and (iii) WHO grade 2–3 oligodendroglioma, IDH-mutant and1p/19q-codeleted (1). Hereafter, these tumors are referred to as glioblastoma, astrocytoma, and oligodendroglioma, respectively. Among these tumor types, median survival is shortest for glioblastoma, the most common of all diffuse gliomas (8–15 months; refs. 2–4), and longest for grade 2 oligoden- 1Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah. 2Department of Radiology, University of Utah, Salt Lake City, Utah. 3Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 4Department of Neurological Surgery, University of Utah, Salt Lake City, Utah. 5Department of Pathology, University of Utah, Salt Lake City, Utah. 6ARUP Laboratories, Salt Lake City, Utah. 7University of Utah School of Medicine, Salt Lake City, Utah. 8Department of Bioengineering, University of Washington, Seattle, Washington. 9Department of Internal Medicine, Division of Oncology, University of Utah, Salt Lake City, Utah. Corresponding Author: Hunter R. Underhill, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, RM LL376, Salt Lake City, UT 8

FAQs

What problem does the study address in sequencing peritumoral edema mutations?

The study addresses the inability to distinguish next-generation sequencing noise from true, weak tumor mutation signals present within peritumoral edema.

What is True2, and what performance does it achieve?

True2 is a sequencing workflow that reduces NGS-associated errors to less than 1 false positive per 100 kb panel positions while detecting 97.6% of somatic mutations with allele frequency ≥0.1%.

What molecular relationship does surgery show between bulk tumors and peritumoral edema?

The tumor and peritumoral edema show similar mutation burden, indicating surgery can debulk cancers physically but not molecularly.

Sep 21, 2026

Uploaded by Lucas Martin