Journal Article

The genomic landscape of schwannoma

Dowar, Mark, Tonge, Peter D, Danesh, Arnavaz, Iavarone, Antonio, Dunn, Ian F, Pagnotta, Stefano M, Alamsahebpour, Amir, Bi, Wenya Linda, Wilson, Mark R, Landon-Brace, Natalie, Krischek, Boris, Bril, Vera, Pugh, Trevor J, Zadeh, Gelareh, Li, Tiantian, Krieger, Jonathan R, Aldape, Kenneth D, Agnihotri, Sameer, Jalali, Shahrzad, Tung, Takyee, Bruce, Jeffrey P, Mansouri, Alireza, Khan, Osaama, Mamatjan, Yasin, Beroukhim, Rameen, Fehlings, Michael G, Klironomos, George, Agarwalla, Pankaj Kumar, Li, Mira, Burrell, Kelly E

2016

Overview

Gelareh Zadeh, Kenneth Aldape and colleagues present an integrative genomic analysis of schwannomas. In addition to finding recurrent mutations in ARID1A , ARID1B and DDR1 , they identify a recurrent SH3PXD2A - HTRA1 fusion that confers increased proliferation, invasion and in vivo transformation, and is associated with sensitivity to MEK inhibition. Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A , ARID1B and DDR1 . RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/22 / 38/90 / 38/91 / 631/208/514/1948 / 631/67/1922 / 82/51 / 82/58 / 96/1 / 96/106 / Adaptor Proteins, Vesicular Transport - genetics / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Cancer / Cancer Research / Care and treatment / Cell Line, Tumor / Cellular signal transduction / Development and progression / DNA Methylation / DNA Mutational Analysis / DNA, Neoplasm / Ear Neoplasms - genetics / Exome / Female / Gene expression / Gene Function / Gene Fusion / Genetic aspects / Genome, Human / Genomes / Genomics / Genotypes / Health aspects / Hearing loss / High-Temperature Requirement A Serine Peptidase 1 / Human Genetics / Humans / Kinases / Male / Mice / Mice, Inbred NOD / Mice, SCID / Mutation / Neurilemmoma - genetics / Neuroectodermal tumors / Proteins / RNA, Neoplasm / Sequence Analysis, DNA / Sequence Analysis, RNA / Serine Endopeptidases - genetics / Spinal Neoplasms - genetics / Studies / Tumors / Vestibule, Labyrinth