EGFR Variant Heterogeneity in Glioblastoma Resolved through Single-Nucleus Sequencing
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Abstract
Glioblastomas (GBM) with EGFR amplification represent approximately 50% of newly diagnosed cases, and recent studies have revealed frequent coexistence of multiple EGFR aberrations within the same tumor, which has implications for mutation cooperation and treatment resistance. However, bulk tumor sequencing studies cannot resolve the patterns of how the multiple EGFR aberrations coexist with other mutations within single tumor cells. Here, we applied a population-based single-cell whole-genome sequencing methodology to characterize genomic heterogeneity in EGFR-amplified glioblastomas. Our analysis effectively identified clonal events, including a novel translocation of a super enhancer to the TERT promoter, as well as subclonal LOH and multiple EGFR mutational variants within tumors. Correlating the EGFR mutations onto the cellular hierarchy revealed that EGFR truncation variants (EGFRvII and EGFR carboxyl-terminal deletions) identified in the bulk tumor segregate into nonoverlapping subclonal populations. In vitro and in vivo functional studies show that EGFRvII is oncogenic and sensitive to EGFR inhibitors currently in clinical trials. Thus, the association between diverse activating mutations in EGFR and other subclonal mutations within a single tumor supports an intrinsic mechanism for proliferative and clonal diversification with broad implications in resistance to treatment. Significance: We developed a novel single-cell sequencing methodology capable of identifying unique, nonoverlapping subclonal alterations from archived frozen clinical specimens. Using GBM as an example, we validated our method to successfully define tumor cell subpopulations containing distinct genetic and treatment resistance profiles and potentially mutually cooperative combinations of alterations in EGFR and other genes. Cancer Discov; 4(8); 956–71. ©2014 AACR. See related commentary by Gini and Mischel, p. 876 This article is highlighted in the In This Issue feature, p. 855
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Single-cell sequencing is becoming common as a research platform but is not yet suitable for clinical use.
“More sensitive approaches of genetic characterization, like single-cell sequencing, are becoming increasingly common as research platforms but are not yet amenable to a clinical setting6, 7.”
From Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate (2016) · cites this paper as [7]
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- Authors
- Francis, J. M., Zhang, C.-Z., Maire, C. L., Jung, J., Manzo, V. E., Adalsteinsson, V. A., Homer, H., Haidar, S., Blumenstiel, B., Pedamallu, C. S., Ligon, A. H., Love, J. C., Meyerson, M., & Ligon, K. L.
- Affiliations
- Broad Institute (US)
- 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Meyerson, Matthew
- Ligon, Keith L.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-08-01
- Volume
- 4
- Issue
- 8
- Pages
- 956-971
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4125473
- OpenAlex
- W2163676912
- Cited by
- 287
- References
- 57
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 12 · 2023: 18 · 2022: 25 · 2021: 25 · 2020: 28 · 2019: 26 · 2018: 26 · 2017: 31 · 2016: 22 · 2015: 38 · 2014: 5
- FWCI
- 16.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- National Cancer Institute (P01CA142536, R01CA116020, R01CA170592, P30CA014051, P50CA165962)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- glioblastoma, EGFR amplification, single-nucleus sequencing, single-cell whole-genome sequencing, tumor subclonal evolution, clonal heterogeneity, super-enhancers, loss of heterozygosity, treatment resistance, EGFR inhibitors, tumor cell hierarchy
- MeSH terms
- Cell Nucleus, Glioblastoma, Humans, Mutation, Genome, Human, Loss of Heterozygosity, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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