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Germline Nonsense Mutation and Somatic Inactivation of SMARCA4/BRG1 in a Family with Rhabdoid Tumor Predisposition Syndrome |
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| Authors: | Reinhard Schneppenheim,Michael C. Frü hwald,Martin Hasselblatt,Uwe Kordes,Ivo Leuschner,Tobias Obser,Inga Vater |
| Affiliation: | 1 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany 2 Research Institute Children's Cancer Center Hamburg, Martinistrasse 52, 20251 Hamburg, Germany 3 Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany, Albert-Schweitzer-Strasse 33, 48149 Muenster, Germany 4 Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 24, 24105 Kiel, Germany 5 Institute of Paidopathology, Pediatric Tumor Registry, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 24, 24105 Kiel, Germany 6 Institute of Neuropathology, University Hospital Muenster, Domagkstrasse 17, 48149 Muenster, Germany 7 Institute of Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany |
| Abstract: | Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to heterozygous SMARCB1 germline mutations. We identified inactivation of another member of the SWI/SNF chromatin-remodeling complex, its ATPase subunit SMARCA4 (also known as BRG1), due to a SMARCA4/BRG1 germline mutation and loss of heterozygosity by uniparental disomy in the tumor cells of two sisters with rhabdoid tumors lacking SMARCB1 mutations. SMARCA4 is thus a second member of the SWI/SNF complex involved in cancer predisposition. Its general involvement in other tumor entities remains to be established. |
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