The genomic landscape of tuberous sclerosis complex

Katie R. Martin, Wanding Zhou, Megan J. Bowman, Juliann Shih, Kit Sing Au, Kristin E. Dittenhafer-Reed, Kellie A. Sisson, Julie Koeman, Daniel J. Weisenberger, Sandra L. Cottingham, Steven T. DeRoos, Orrin Devinsky, Mary E. Winn, Andrew D. Cherniack, Hui Shen, Hope Northrup, Darcy A. Krueger and Jeffrey P. MacKeigan ()
Additional contact information
Katie R. Martin: Center for Cancer and Cell Biology, Van Andel Research Institute
Wanding Zhou: Center for Epigenetics, Van Andel Research Institute
Megan J. Bowman: Bioinformatics and Biostatistics Core, Van Andel Research Institute
Juliann Shih: Cancer Program, Broad Institute of Harvard and MIT
Kit Sing Au: University of Texas Health Science Center at Houston-McGovern Medical School
Kristin E. Dittenhafer-Reed: Center for Cancer and Cell Biology, Van Andel Research Institute
Kellie A. Sisson: Center for Cancer and Cell Biology, Van Andel Research Institute
Julie Koeman: Cytogenetics and Pathology Core, Van Andel Research Institute
Daniel J. Weisenberger: Norris Comprehensive Cancer Center, University of Southern California
Sandra L. Cottingham: Spectrum Health System
Steven T. DeRoos: Helen DeVos Children’s Hospital, Spectrum Health System
Orrin Devinsky: New York University School of Medicine
Mary E. Winn: Bioinformatics and Biostatistics Core, Van Andel Research Institute
Andrew D. Cherniack: Cancer Program, Broad Institute of Harvard and MIT
Hui Shen: Center for Epigenetics, Van Andel Research Institute
Hope Northrup: University of Texas Health Science Center at Houston-McGovern Medical School
Darcy A. Krueger: Cincinnati Children’s Hospital Medical Center
Jeffrey P. MacKeigan: Center for Cancer and Cell Biology, Van Andel Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15816

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