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High‐resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis
Author(s) -
Paulson Vera,
Chandler Garvin,
Rakheja Dinesh,
Galindo Rene L.,
Wilson Kathleen,
Amatruda James F.,
Cameron Scott
Publication year - 2011
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20864
Subject(s) - cdkn2a , biology , cancer research , gli1 , comparative genomic hybridization , embryonal rhabdomyosarcoma , receptor tyrosine kinase , rhabdomyosarcoma , genetics , cancer , transcription factor , gene , signal transduction , sarcoma , pathology , medicine , genome
Pediatric rhabdomyosarcoma occurs as two biologically distinct histological variants, embryonal (ERMS) and alveolar (ARMS). To identify genomic changes that drive ERMS pathogenesis, we used a new array comparative genomic hybridization (aCGH) platform to examine a specific subset of ERMS tumors, those occurring in children with clinically defined intermediate‐risk disease. The aCGH platform used has an average probe spacing ∼1 kb, and can identify genomic changes with single gene resolution. Our data suggest that these tumors share a common genomic program that includes inactivation of a master regulator of the p53 and Rb pathways, CDKN2A/B , and activation of FGFR4 , Ras, and Hedgehog (Hh) signaling. The CDKN2A/B tumor suppressor is deleted in most patient samples. FGFR4 , which encodes a receptor tyrosine kinase, is activated in 20% of tumors, predominantly by amplification of mutant, activating FGFR4 alleles. Over 50% of patients had low‐level gains of a region containing the Hh‐pathway transcription factor GLI1 , and a gene expression pattern consistent with Hh‐pathway activation. We also identified intragenic deletions affecting NF1 , a tumor suppressor and inhibitor of Ras, in 15% of tumor samples. Deletion of NF1 and the presence of activating Ras mutations (in 42% of patients) were mutually exclusive, suggesting NF1 loss is an alternative and potentially common mechanism of Ras activation in ERMS. Our data suggest that intermediate‐risk ERMS is driven by a common set of genomic defects, a finding that has important implications for the application of targeted therapies to improve the treatment of children diagnosed with this disease. © 2011 Wiley‐Liss, Inc.