[47] FBXW7 Mutations in a Subset of Embryonal Rhabdomyosarcoma

Erick Jacobson-Dunlop, Atiya Mansoor, Christopher Corless, Michael Heinrich, Carol Beadling. Oregon Health and Science University, Portland, OR

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children under 15 years of age. Histologic subtypes correlate not only with prognosis, but also with well-described cytogenetic abnormalities. Little is known, however, concerning the frequency of mutations in RMS of cancer genes known to play a significant role in other malignancies.
Design: Thirty archival rhabdomyosarcomas were reviewed and histologically sub-classified. There were 13 embryonal RMS, 8 alveolar RMS and 9 unclassified. Cytogenetic information available from the time of diagnosis was also compiled. DNA was prepared from formalin fixed, paraffin-embedded tumor tissue (>90% tumor), and screened for mutations using a multiplexed assay panel with a mass spectrometry-based readout that covers 390 mutations across 30 cancer genes.
Results: Mutations in one or multiple cancer genes were observed in 5 of the 30 cases (17%) and were seen only in the embryonal subtype (5/12, 41.7%). Of note, a FBXW7 R465C and a FBXW7 R505C mutation, not previously described in rhabdomyosarcomas, was present in two of the embryonal cases. Additional mutations included NRAS Q61H and Q61P (2/30, 6.7% of all cases; 2/12, 16.7% of embryonal RMS), KRAS G12C (1/30, 3.3%; 1/12, 8.3%) and FGFR4 V550M (1/30, 3.3%; 1/12, 8.3%), all of which have been previously described in RMS. No mutations were observed in any of the alveolar RMS (0/8), irrespective of cytogenetic abnormalities.
Conclusions: FGFR4 is a potential treatment target in embryonal RMS, and routine genotyping of this subset of tumors could help identify patients for clinical trials. FBXW7 is a member of the F-box family and serves as part of the ubiquitin protein ligase complex that regulates degradation of MYC, cyclin E and MCL1. The finding of recurrent mutations in this gene suggests a significant role in deregulation of gene transcription, apoptosis, and the cell cycle in embryonal RMS.
Category: Bone & Soft Tissue

Monday, March 19, 2012 1:00 PM

Poster Session II # 35, Monday Afternoon


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