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Linked-read Sequencing Analysis Reveals Tumor-specific Genome Variation Landscapes in Neurofibromatosis Type 2 (NF2) Patients

Roberts, Daniel S.*; Maurya, Rahul; Takemon, Yuka‡,§; Vitte, Jeremie||; Gong, Liang; Zhao, Juanjuan; Wong, Chee-Hong; Slattery, William; Peng, Kevin A.; Lekovic, Gregory; Schwartz, Marc S.**; Bulsara, Ketan*; Ngan, Chew Yee; Giovannini, Marco||; Wei, Chia-Lin

doi: 10.1097/MAO.0000000000002096

Hypothesis: We hypothesize that genomic variants including deletions, insertions, inversions, and tandem duplications beyond the changes in tumor suppressor NF2 gene affect gene expression of tumor-specific pathways in vestibular schwannomas (VS) patients with Neurofibromatosis type 2 (NF2), thus contributing to their clinical behavior.

Background: Genomic variation could reconfigure transcription in NF2 transformation process. Therefore, genome-wide high-resolution characterization of structural variants (SV) landscapes in NF2 tumors can expand our understanding of the genes regulating the clinical phenotypes in NF2-associated VS.

Methods: We performed whole-genome haplotype-specific structural variation analysis using synthetic linked reads generated through microfluidics-based barcoding of high molecular weight DNA followed by high-coverage Illumina paired-end whole-genome sequencing from 10 patients’ tumors of different growth rates and their matching blood samples.

Results: NF2 tumor-specific deletions and large SVs were detected and can be classified based on their association with tumor growth rates. Through detailed annotation of these mutations, we uncover common alleles affected by these deletions and large SVs that can be associated with signaling pathways implicated in cell proliferation and tumorigenesis.

Conclusion: The genomic variation landscape of NF2-related VS was investigated through whole-genome linked-read sequencing. Large SVs, in addition to deletions, were identified and may serve as modulators of clinical behavior.

*School of Medicine, University of Connecticut

The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut

The Jackson Laboratory, Bar Harbor

§Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine

||Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles

House Clinic and House Ear Institute, Los Angeles

**University of California, San Diego, San Diego, California

Address correspondence and reprint requests to Daniel S. Roberts, M.D., Ph.D., 263 Farmington Avenue, Farmington, CT 06030; E-mail:; Chia-Lin Wei, Ph.D., 10 Discovery Drive, Farmington, CT 06032; E-mail:

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

D.S.R and R.M. contributed equally to this work.

Y.T. and J.V. contributed equally to this work.

M.S.S., M.D., is a consultant and receives grant support from Cochlear Corporation for unrelated projects. Research reported in this publication was supported by the House Ear Institute and the National Cancer Institute of the National Institutes of Health under Award Number P30CA034196.

The authors disclose no conflicts of interest.

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