Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways Journal Article
| Authors: | Shukla, N.; Ameur, N.; Yilmaz, I.; Nafa, K.; Lau, C. Y.; Marchetti, A.; Borsu, L.; Barr, F. G.; Ladanyi, M. |
| Article Title: | Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways |
| Abstract: | Purpose: 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). Experimental Design: 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. ©2011 AACR. |
| Keywords: | signal transduction; controlled study; human tissue; unclassified drug; gene mutation; raf protein; cancer patient; gene function; ewing sarcoma; oncogene; neuroblastoma; dna sequence; beta catenin; dna extraction; b raf kinase; pik3ca gene; oncogene ras; genomic dna; embryonal rhabdomyosarcoma; gene activity; desmoplastic small round cell tumor; braf gene; fibroblast growth factor receptor 4; map2k1 gene; calcium calmodulin dependent protein kinase; microtubule associated protein 2 kinase 1; ctnnb1 gene |
| Journal Title: | Clinical Cancer Research |
| Volume: | 18 |
| Issue: | 3 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-02-01 |
| Start Page: | 748 |
| End Page: | 757 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-11-2056 |
| PROVIDER: | scopus |
| PMCID: | PMC3271129 |
| PUBMED: | 22142829 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 March 2012" - "CODEN: CCREF" - "Source: Scopus" |
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