Human Molecular Genetics Advance Access originally published online on December 12, 2006
Human Molecular Genetics 2007 16(4):374-379; doi:10.1093/hmg/ddl458
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Uniparental disomy at chromosome 11p15.5 followed by HRAS mutations in embryonal rhabdomyosarcoma: lessons from Costello syndrome
1 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany, 2 Institute of Cell and Molecular Pathology, Hannover Medical School, 30623 Hannover, Germany, 3 Department of Pediatric Hematology and Oncology, Olgahospital, 70031 Stuttgart, Germany and 4 Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
* To whom correspondence should be addressed. Tel: +49 761 270 4514; Fax: +49 761 270 4518; Email: christian.kratz{at}uniklinik-freiburg.de
Received August 20, 2006; Revised September 25, 2006; Accepted December 5, 2006
Costello syndrome (CS; MIM 218040 [OMIM] ) is characterized by short stature, facial dysmorphism, cardiac defects and predisposition to embryonal rhabdomyosarcoma (CS/ERMS) and other neoplasias. CS is caused by germline mutations in the HRAS gene on chromosome 11p15.5, a region showing allelic imbalances in sporadic ERMS and CS/ERMS. The critical gene for ERMS development in this region is unknown. The association of CS and ERMS as well as previous reports illustrating that somatic HRAS mutations are found in a proportion of these tumors prompted us to clarify the significance and a possible correlation of HRAS mutations and genomic rearrangements at 11p15.5 in sporadic ERMS. We screened for somatic HRAS mutations and 11p15.5 imbalances in six sporadic ERMS samples. This analysis uncovered five ERMS samples with uniparental disomy (UPD) at the HRAS locus, two of which harbored HRAS mutations. By analyzing informative genetic variations in or at the HRAS gene locus, we show that one HRAS allele is entirely lost in specimens with UPD at 11p15.5. Notably, in both cases with UPD and HRAS mutations these mutations were heterozygous. Therefore, they must have succeeded the emergence of UPD. In contrast, HRAS germline mutations are the first step in CS/ERMS. Subsequent development of UPD at 11p15.5 may explain previous observations that CS/ERMS express mutant HRAS only. These data implicate that in sporadic ERMS, UPD at 11p15.5 is not driven by HRAS mutations and that imbalances at 11p15.5 and HRAS mutations represent independent but cooperating events during ERMS development.
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in Hum. Mol. Genet.:
- Uniparental disomy at chromosome 11p15.5 followed by HRAS mutations in embryonal rhabdomyosarcoma: lessons from Costello syndrome
- Christian P. Kratz, Doris Steinemann, Charlotte M. Niemeyer, Brigitte Schlegelberger, Ewa Koscielniak, Udo Kontny, and Martin Zenker
Hum. Mol. Genet. 2007 10.1093/hmg/ddm230.[Extract] [FREE Full Text]
This article has been cited by other articles:
|
|
 |
|
  F. G. Barr and W. H. Meyer Rhabdomyosarcoma: An Overview of Biology, Clinical Features, and the Current Children's Oncology Group Studies ASCO Educational Book, January 1, 2008; 2008(1): 465 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Slater and J. Shipley Clinical relevance of molecular genetics to paediatric sarcomas J. Clin. Pathol., November 1, 2007; 60(11): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|