Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.
Top Cited Papers
- 28 February 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 4 (2), 216-31
- https://doi.org/10.1158/2159-8290.cd-13-0639
Abstract
Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma. Significance: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention. Cancer Discov; 4(2); 216–31. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 131Other Versions
This publication has 67 references indexed in Scilit:
- Medulloblastoma exome sequencing uncovers subtype-specific somatic mutationsNature, 2012
- Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancerNature Genetics, 2012
- A novel retinoblastoma therapy from genomic and epigenetic analysesNature, 2012
- The genetic basis of early T-cell precursor acute lymphoblastic leukaemiaNature, 2012
- Frequent mutation of histone-modifying genes in non-Hodgkin lymphomaNature, 2011
- Initial genome sequencing and analysis of multiple myelomaNature, 2011
- Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiationNature Biotechnology, 2010
- Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975‐2005Cancer, 2009
- Genomic and clinical analyses of 2p24 and 12q13‐q14 amplification in alveolar rhabdomyosarcoma: A report from the Children's Oncology GroupGenes, Chromosomes and Cancer, 2009
- PAX3–FOXO1 fusion gene in rhabdomyosarcomaCancer Letters, 2008