Journal Article

Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis

Watson, Adrienne L, Wolf, Natalie K, Ratner, Nancy, Moertel, Christopher L, Moriarity, Branden S, Wallace, Margaret R, Sarver, Aaron, Gel, Bernat, Beckmann, Dominic A, Keng, Vincent W, Rahrmann, Eric P, Largaespada, David A, Serra, Eduard, Choi, Kwangmin, Collins, Margaret H

2013

Overview

Eric Rahrmann and colleagues performed a transposon-based somatic mutagenesis screen for genes involved in malignant peripheral nerve sheath tumors (MPNSTs). They identified many recurrent transposon insertions and nominate Foxr2 as a new oncogene in MPNSTs. Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty ( SB ) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 ( Trp53 ) function and/or overexpression of human epidermal growth factor receptor ( EGFR ). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/β-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/199 / 692/699/1798 / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Cancer / Cancer Research / Cell cycle / Cell Line, Tumor / Cell Transformation, Neoplastic - genetics / Colleges & universities / DNA Mutational Analysis / DNA Transposable Elements - genetics / Epidermal growth factor / Gene amplification / Gene Function / Genes, Neoplasm - physiology / Genetic aspects / Genetic Association Studies / Genetic screening / Genetic Testing - methods / Genetics / Genomes / Health aspects / Human Genetics / Humans / Kinases / Mice / Mice, Transgenic / Mutagenesis / Mutation / Mutation - physiology / Nerve Sheath Neoplasms - genetics / Neurofibroma - genetics / Physiological aspects / Sarcoma / Signal Transduction - genetics / Statistical methods / Tumor proteins