期刊
CANCER DISCOVERY
卷 12, 期 1, 页码 172-185出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0245
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资金
- Basic Research Fellowship from the American Brain Tumor Association [BRF1900016]
- Harvard/MIT MD-PhD MSTP program [T32GM007753]
- Biomedical Informatics and Data Science Training Program [T15LM007092]
- Ruth L. Kirschstein NRSA F31 Fellowship [F31MH124292]
- NHGRI T32 Training Grant [5T32HG002295-18]
- NIH [R01CA188228, R01CA215489, P50CA165962, K01 AG051791, DP2 AG072437]
- Pediatric Brain Tumor Foundation
- PLGA Foundation
- NINDS [R01 NS032457]
- NIMH [U01 MH106883]
- NIA [R01AG070921]
- Allen Discovery Center program through The Paul G. Allen Frontiers Group
- Boston Children's Hospital IDDRC Molecular Genetics Core Facility by NIH award from the National Institute of Child Health and Human Development [U54HD090255]
- NCI-Brain Cancer SPORE [P50CA165962]
- Suh Kyungbae Foundation
Although oncogenic mutations have been found in non-diseased, proliferative non-neural tissues, their prevalence in the human brain is unknown. This study identified oncogenic somatic single-nucleotide variants (sSNVs) in the brains of individuals without tumor diagnoses, with a higher frequency in subcortical white matter and glial cells, and a lower frequency in older individuals. The study also revealed early events in acquiring oncogenic variants, which can contribute to understanding brain tumor origins and improving diagnostics.
Although oncogenic mutations have been found in nondiseased, proliferative non- neural 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 IDH1(R132H). 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.
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