In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 20_Supplement ( 2014-10-15), p. A21-A21
Abstract:
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. With the development of multimodal chemotherapy regimens, relapse-free survival rates have improved to 70-80% in patients with localized disease albeit with significant toxicity. Despite these gains, survival for those patients with metastatic or recurrent disease remains dismal. Further characterization of the genetic events underlying this tumor type is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. In a collaborative effort between the National Cancer Institute, the Children's Oncology Group, and the Broad Institute, we used a combination of whole-genome, whole-exome and transcriptome sequencing along with high resolution SNP arrays to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two distinct genotypes are evident in RMS tumors; those characterized by the PAX3 or PAX7 fusion proteins that includes novel fusions with cryptic partners (35% of cases) and those that lack a PAX3/7 fusion but harbor mutations in key signaling pathways (65% of cases). Consistent with other pediatric cancer types, the overall burden of somatic mutations in RMS is relatively low (0.31 somatic protein coding mutations per megabase) especially in tumors that harbor a PAX3/7 gene fusion (0.1 somatic mutations per megabase). In addition to genes previously reported as altered in RMS including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1 we discovered novel recurrent mutations in FBXW7, and the chromatin remodeling gene BCOR, which provide new potential avenues for therapeutic intervention. Transcriptome analysis showed that 58% of the verified genomic mutations were expressed with a marked enrichment in cell cycle (P=2e-6), protein phoshorylation (P=6.9e-5) and muscle cell differentiation (P=3.3e-4) and many of the tumors appear to accumulate multiple genetic hits within these same pathways. Finally, we identify alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of RMS cases which provides a framework for genomics-directed therapies that might improve outcomes for RMS patients. Citation Format: Jack F. Shern, Li Chen, Juliann Chmielecki, Jun Wei, Rajesh Patidar, Young Song, Hongling Liao, Andy Brohl, Daniel Catchpoole, Thomas Badgett, Gad Getz, Jaume Graupera, James Anderson, Stephen X. Skapek, Frederic G. Barr, Douglas S. Hawkins, Javed Khan. Integrative genome and transcriptome sequencing defines the landscape of genetic alterations underlying pediatric rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A21.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.PEDCAN-A21
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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