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Cited by 238Tuberous Sclerosis Complex ResearchCancer Genomics and DiagnosticsPI3K/AKT/mTOR signaling in cancer

The genomic landscape of tuberous sclerosis complex

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Martin, Katie R., Zhou, Wanding, Bowman, Megan J., Shih, Juliann, Au, Kit Sing, Dittenhafer-Reed, Kristin E., Sisson, Kellie A., Koeman, Julie +10 more·2017·Nature Communications
DOI 10.1038/ncomms15816PMC PMC5481739
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Abstract

Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours.

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  • Gene-expression analysis of tuber tissue has revealed increased expression of astrocyte-enriched genes and prominent neuroinflammation.

    “Indeed, gene-expression analysis of tuber tissue has revealed increased expression of astrocyte-enriched genes and prominent neuroinflammation14,15.”

    From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [14]

    The Results section, “Brain lesions show evidence of significant neuroinflammation” (page unavailable), reports increased expression of immune- and inflammation-related genes in cortical tubers. It does not report increased expression of astrocyte-enriched genes in tubers; its cell-type analysis instead estimates an astrocyte proportion similar to normal brain tissue. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Second-hit mutations are frequently observed in TSC-related hamartomas and have been identified in some resected tubers from patients.

    “Second-hit mutations are frequently observed in TSC-related hamartomas and have been identified in some resected tubers from patients14,21,22,23.”

    From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [14]

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Authors
Martin, K. R., Zhou, W., Bowman, M. J., Shih, J., Au, K. S., Dittenhafer-Reed, K. E., Sisson, K. A., Koeman, J., Weisenberger, D. J., Cottingham, S. L., DeRoos, S. T., Devinsky, O., Winn, M. E., Cherniack, A. D., Shen, H., Northrup, H., Krueger, D. A., & MacKeigan, J. P.
Affiliations
  • Van Andel Institute (US)
  • Broad Institute (US)
  • The University of Texas Health Science Center at Houston (US)
  • University of Southern California (US)
  • Spectrum Health (US)
  • New York University (US)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
MacKeigan, Jeffrey P.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-06-15
Volume
8
Issue
1
Pages
15816-15816
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms15816
PMC
PMC5481739
OpenAlex
W2626329567
Cited by
238
References
69
Citations by year
2026: 18 · 2025: 34 · 2024: 22 · 2023: 29 · 2022: 26 · 2021: 34 · 2020: 27 · 2019: 29 · 2018: 14 · 2017: 4
FWCI
14.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Tuberous Sclerosis Alliance (U01-NS082320, U54-NS092090)
  • Van Andel Research Institute
  • McGovern Medical School
  • National Institutes of Health
  • U.S. Food and Drug Administration
  • National Cancer Institute (R01CA197398)
  • National Institute of Neurological Disorders and Stroke (U01NS082320, P20NS080199, NS082320, U54NS092090)
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
tuberous sclerosis complex, hamartoma, TSC1 mutation, TSC2 mutation, chromosomal abnormalities, molecular signatures, cellular heterogeneity, cell of origin, neuroinflammation, brain tumors, mTOR activation, cancer genomics
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Carcinoma, Humans, Mutation, Tuberous Sclerosis, Genomics, Tumor Suppressor Proteins

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