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Cited by 48Cancer Genomics and DiagnosticsGlioma Diagnosis and TreatmentAcute Myeloid Leukemia Research

Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain

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Ganz, Javier, Maury, Eduardo A., Becerra, Basheer, Bizzotto, Sara, Doan, Ryan N., Kenny, Connor J., Shin, Taehwan, Kim, Junho +4 more·2022·Cancer Discovery
DOI 10.1158/2159-8290.cd-21-0245PMC PMC8758513

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Abstract

Although oncogenic mutations have been found in nondiseased, proliferative nonneural tissues, their prevalence in the human brain is unknown. Targeted sequencing of genes implicated in brain tumors in 418 samples derived from 110 individuals of varying ages, without tumor diagnoses, detected oncogenic somatic single-nucleotide variants (sSNV) in 5.4% of the brains, including IDH1R132H. These mutations were largely present in subcortical white matter and enriched in glial cells and, surprisingly, were less common in older individuals. A depletion of high-allele frequency sSNVs representing macroscopic clones with age was replicated by analysis of bulk RNA sequencing data from 1,816 nondiseased brain samples ranging from fetal to old age. We also describe large clonal copy number variants and that sSNVs show mutational signatures resembling those found in gliomas, suggesting that mutational processes of the normal brain drive early glial oncogenesis. This study helps understand the origin and early evolution of brain tumors. Significance: In the nondiseased brain, clonal oncogenic mutations are enriched in white matter and are less common in older individuals. We revealed early steps in acquiring oncogenic variants, which are essential to understanding brain tumor origins and building new mutational baselines for diagnostics. This article is highlighted in the In This Issue feature, p. 1

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  • UMI-based panel sequencing detects somatic variants with variant allele fractions as low as 0.1% with much higher sensitivity and precision than previous methods not employing consensus error correction.

    “By generating a consensus sequence from multiple reads derived from the same original DNA molecule, UMI-based panel sequencing exponentially reduces base-calling errors and detects somatic variants with VAFs as low as 0.1% (Figure S1C–D), with much higher sensitivity and precision than previous methods not employing consensus error correction30.”

    From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [30]

    The Results (Identification of Variants from Deep-Targeted Sequencing; page unavailable) limit the analyzed variants to 0.5%–15% VAF and report sensitivity comparable to other studies, not much higher. The Discussion (page unavailable) says sensitivity at 0.5% VAF was approximately 10% and that detecting still-lower-frequency events remained challenging, contrary to the claimed 0.1% detection capability. (LLM, conf=0.88)

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Authors
Ganz, J., Maury, E. A., Becerra, B., Bizzotto, S., Doan, R. N., Kenny, C. J., Shin, T., Kim, J., Zhou, Z., Ligon, K. L., Lee, E. A., & Walsh, C. A.
Affiliations
  • Broad Institute (US)
  • Boston Children's Hospital (US)
Corresponding author
  • Lee, Eunjung Alice
  • Walsh, Christopher A.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-08-13
Volume
12
Issue
1
Pages
172-185
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-21-0245
PMC
PMC8758513
OpenAlex
W3190166921
Cited by
48
References
10
Citations by year
2026: 12 · 2025: 9 · 2024: 11 · 2023: 9 · 2022: 7
FWCI
2.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Discovery (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • American Brain Tumor Association (BRF1900016)
  • National Cancer Institute (P50CA165962)
  • Harvard/MIT MD-PhD MSTP Program (T32GM007753)
  • Biomedical Informatics and Data Science Training Program (T15LM007092)
  • Ruth Kirschstein NRSA F31 Fellowship (F31MH124292)
  • National Institutes of Health (R01CA188228, R01CA215489, P50CA165962, K01 AG051791, DP2 AG072437)
  • Pediatric Brain Tumor Foundation
  • Pediatric Low Grade Astrocytoma Foundation
  • Suh Kyungbae Foundation
  • National Institute of Neurological Disorders and Stroke (R01 NS032457)
  • National Institute of Mental Health (U01 MH106883)
  • National Institute on Aging (R01AG070921)
  • Allen Discovery Center - Paul G. Allen Frontiers Group
  • Howard Hughes Medical Institute
  • National Human Genome Research Institute (5T32HG002295-18)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
normal human brain, IDH1 R132H mutation, somatic single nucleotide variants, copy number variation, mutational signatures, white matter, glioma
MeSH terms
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Brain, Brain Neoplasms, Child, Child, Preschool, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Oncogenes, Polymorphism, Single Nucleotide, Young Adult

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