High‐resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis

Abstract

Pediatric rhabdomyosarcoma occurs as two biologically distinct histological variants, embryonal (ERMS) and alveolar (ARMS). To identify genomic changes that drive ERMS pathogenesis, we used a new array comparative genomic hybridization (aCGH) platform to examine a specific subset of ERMS tumors, those occurring in children with clinically defined intermediate-risk disease. The aCGH platform used has an average probe spacing ∼1 kb, and can identify genomic changes with single gene resolution. Our data suggest that these tumors share a common genomic program that includes inactivation of a master regulator of the p53 and Rb pathways, CDKN2A/B, and activation of FGFR4, Ras, and Hedgehog (Hh) signaling. The CDKN2A/B tumor suppressor is deleted in most patient samples. FGFR4, which encodes a receptor tyrosine kinase, is activated in 20% of tumors, predominantly by amplification of mutant, activating FGFR4 alleles. Over 50% of patients had low-level gains of a region containing the Hh-pathway transcription factor GLI1, and a gene expression pattern consistent with Hh-pathway activation. We also identified intragenic deletions affecting NF1, a tumor suppressor and inhibitor of Ras, in 15% of tumor samples. Deletion of NF1 and the presence of activating Ras mutations (in 42% of patients) were mutually exclusive, suggesting NF1 loss is an alternative and potentially common mechanism of Ras activation in ERMS. Our data suggest that intermediate-risk ERMS is driven by a common set of genomic defects, a finding that has important implications for the application of targeted therapies to improve the treatment of children diagnosed with this disease.

Characterization of genetic lesions in rhabdomyosarcoma using a high‐density single nucleotide polymorphism array

“…(5,(7)(8)(9) Although these genetic findings suggest that the two subtypes represent discrete clinicopathological entities, their molecular basis has not been completely elucidated.…”

Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

“…This is corroborated by another study showing absence of PTCH1 loss-of-function mutations or SMO amplifications in 26 NRMS examined [41]. Also, a recent whole-genome sequencing (WGS) analysis on 16 RMS tumors ruled out the presence of mutations in components of the Hh pathway [48].…”

“…Subsequently, the generation of mice heterozygous for Ptch confirmed the involvement of Hh pathway over-activation in RMS tumorigenesis [38]. Accordingly, up-regulation of Hh target genes such as GLI1 and PTCH1 has been demonstrated by retrospective analysis of RMS patient samples or in human RMS cell lines [39][40][41][42][43]. Additionally, activation of Hh pathway seems to be specific for fusion negative RMS (NRMS) and significantly identifies patients with poor prognosis [40,41,44,45].…”

“…Accordingly, up-regulation of Hh target genes such as GLI1 and PTCH1 has been demonstrated by retrospective analysis of RMS patient samples or in human RMS cell lines [39][40][41][42][43]. Additionally, activation of Hh pathway seems to be specific for fusion negative RMS (NRMS) and significantly identifies patients with poor prognosis [40,41,44,45]. Despite this recognized role of Hh in RMS, the contribution of the ligand-based signaling versus non-canonical pathway activation in sporadic RMS is still unclear.…”

“…Also, a recent whole-genome sequencing (WGS) analysis on 16 RMS tumors ruled out the presence of mutations in components of the Hh pathway [48]. SHH immunoreactivity is not common in RMS and the higher Hh activity in NRMS compared to fusion positive RMS (PRMS) does not correlate with SHH mRNA levels, which are unchanged between the two subtypes [39][40][41]. However, we previously found a positive correlation of IHH and DHH mRNA levels with the expression of Hh target genes in RMS supporting the hypothesis of a ligand-mediated activation of Hh pathway [45].…”