Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: A report from the Children's Oncology Group

Background Aberrant activation of the hedgehog (Hh) signaling pathway is implicated widely in both pediatric and adult malignancies. Inactivation of the Hh regulator PTCH is responsible for the Gorlin cancer predisposition syndrome. The spectrum of tumors found in Gorlin Syndrome includes basal cell...

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Bibliographic Details
Published in:Pediatric blood & cancer 2011-12, Vol.57 (6), p.930-938
Main Authors: Pressey, Joseph G., Anderson, James R., Crossman, David K., Lynch, James C., Barr, Frederic G.
Format: Article
Language:English
Subjects:
Cell Line, Tumor
GLI
Gorlin's syndrome
hedgehog
Hedgehog Proteins - metabolism
Humans
Oligonucleotide Array Sequence Analysis
Patched Receptors
Patched-1 Receptor
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
rhabdomyosarcoma
Rhabdomyosarcoma - genetics
Rhabdomyosarcoma - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sarcoma - genetics
Sarcoma - metabolism
Signal Transduction
Transcription Factors - genetics
Transcription Factors - metabolism
undifferentiated sarcoma
Zinc Finger Protein GLI1
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Summary:Background Aberrant activation of the hedgehog (Hh) signaling pathway is implicated widely in both pediatric and adult malignancies. Inactivation of the Hh regulator PTCH is responsible for the Gorlin cancer predisposition syndrome. The spectrum of tumors found in Gorlin Syndrome includes basal cell carcinoma, medulloblastoma, and rarely, rhabdomyosarcoma (RMS). A previous report utilizing in situ hybridization has provided initial evidence for the expression of Hh targets GLI1 and PTCH in RMS tumors. Procedure To investigate the role of Hh pathway signaling in pediatric RMS and undifferentiated sarcoma (US) tumors, the expression of Hh pathway targets GLI1 and PTCH was measured. RNA was extracted from archival human tumor specimens collected from pediatric patients enrolled on Intergroup Rhabdomyosarcoma Study III and IV, and subjected to quantitative reverse transcriptase‐polymerase chain reaction. Results Expression of GLI1 with or without PTCH was detected in substantial subsets of embryonal RMS (ERMS) and US tumors but only rarely in alveolar RMS tumors. Neither PTCH mutations nor activating SMO mutations were detected in ERMS tumors with high GLI1 expression. Microarray analysis demonstrated relative overexpression of downstream Hh targets in ERMS tumors with high or intermediate GLI1 expression. Unlike a recent report, Hh pathway activity in ERMS tumors did not correlate with a unique clinical phenotype. Conclusions Our findings support a role for Hh pathway activation in the genesis of a subset of ERMS and US tumors. Hh signaling may represent a novel therapeutic target in affected tumors. Pediatr Blood Cancer 2011; 57: 930–938. © 2011 Wiley‐Liss, Inc.
ISSN:1545-5009
1545-5017
DOI:10.1002/pbc.23174