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Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. | LitMetric

Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.

Cancer Discov

1Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, NIH; 2Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland; 3Broad Institute of MIT and Harvard, Cambridge; 4Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute; 5Department of Pathology, Harvard Medical School, Boston, Massachusetts; 6University of Nebraska Medical Center, Omaha, Nebraska; 7Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; and 8Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington; 9The Tumour Bank, The Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; 10Department of Oncology, Hospital Sant Joan de Deu de Barcelona, Barcelona, Spain.

Published: February 2014

Unlabelled: 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462130PMC
http://dx.doi.org/10.1158/2159-8290.CD-13-0639DOI Listing

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