title: Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways.
abstract: OBJECTIVE
  In contrast to the numerous broad screens for oncogene mutations in adult cancers, few such screens have been conducted in pediatric solid tumors. To identify novel mutations and potential therapeutic targets in pediatric cancers, we conducted a high-throughput Sequenom-based analysis in large sets of several major pediatric solid cancers, including neuroblastoma, Ewing sarcoma, rhabdomyosarcoma (RMS), and desmoplastic small round cell tumor (DSRCT).
  
  
  METHODS
  We designed a highly multiplexed Sequenom-based assay to interrogate 275 recurrent mutations across 29 genes. Genomic DNA was extracted from 192 neuroblastoma, 75 Ewing sarcoma, 89 RMS, and 24 DSRCT samples. All mutations were verified by Sanger sequencing.
  
  
  RESULTS
  Mutations were identified in 13% of neuroblastoma samples, 4% of Ewing sarcoma samples, 21.1% of RMS samples, and no DSRCT samples. ALK mutations were present in 10.4% of neuroblastoma samples. The remainder of neuroblastoma mutations involved the BRAF, RAS, and MAP2K1 genes and were absent in samples harboring ALK mutations. Mutations were more common in embryonal RMS (ERMS) samples (28.3%) than alveolar RMS (3.5%). In addition to previously identified RAS and FGFR4 mutations, we report for the first time PIK3CA and CTNNB1 (β-catenin) mutations in 5% and 3.3% of ERMS, respectively.
  
  
  CONCLUSIONS
  In ERMS, Ewing sarcoma, and neuroblastoma, we identified novel occurrences of several oncogene mutations recognized as drivers in other cancers. Overall, neuroblastoma and ERMS contain significant subsets of cases with nonoverlapping mutated genes in growth signaling pathways. Tumor profiling can identify a subset of pediatric solid tumor patients as candidates for kinase inhibitors or RAS-targeted therapies.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Neerav
authors.initials: N
authors.lastname: Shukla
authors.forename: Nabahet
authors.initials: N
authors.lastname: Ameur
authors.forename: Ismail
authors.initials: I
authors.lastname: Yilmaz
authors.forename: Khedoudja
authors.initials: K
authors.lastname: Nafa
authors.forename: Chyau-Yueh
authors.initials: CY
authors.lastname: Lau
authors.forename: Angela
authors.initials: A
authors.lastname: Marchetti
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Barr
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D049109:Cell Proliferation; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D058405:Desmoplastic Small Round Cell Tumor / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D021141:Nucleic Acid Amplification Techniques; D016133:Polymerase Chain Reaction; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000473:pathology; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm