Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome.
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.
Schneppenheim
Reinhard
R
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. schneppenheim@uke.de
Frühwald
Michael C
MC
Gesk
Stefan
S
Hasselblatt
Martin
M
Jeibmann
Astrid
A
Kordes
Uwe
U
Kreuz
Markus
M
Leuschner
Ivo
I
Martin Subero
Jose Ignacio
JI
Obser
Tobias
T
Oyen
Florian
F
Vater
Inga
I
Siebert
Reiner
R
D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics*; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000473:pathology; D013577:Syndrome; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
D018389:Codon, Nonsense; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases