Identification and analysis of tumor suppressor loci at chromosome 10q23.3-10q25.3 in medulloblastoma.
Abnormalities of chromosome 10 are frequently observed in the development of medulloblastoma, the most common malignant brain tumor of childhood. To identify critical genetic loci involved, we performed detailed physical mapping of regions of allelic loss on this chromosome. 18% of cases (5/32 primary tumors, 2/8 cell lines) harbored allelic losses on 10q. Refined mapping identified a 21.7Mb common interval, affecting the region 10q23.3-10q25.3. This region contains three genes, MXI1, SUFU and BTRC, which represent putative medulloblastoma tumor suppressor (TS) genes on the basis of either (i) negative regulation of critical medulloblastoma pathways, or (ii) mutation in other cancer types. We therefore sought evidence of their genetic inactivation in 46 cases, by mutational analysis of their entire coding regions. A MXI1 mutation was identified which abolishes its translation initiation site (A1G; MET1VAL), however no further tumor-specific sequence variations were detected. We next identified and characterised CpG islands associated with 5' regions of the MXI1, SUFU and BTRC genes; analysis of these regions for evidence of DNA hypermethylation, alongside expression analysis of their respective transcripts, revealed no evidence to support epigenetic inactivation of any gene. These findings implicate the inactivation of critical TS loci at 10q23.3-25.3 in medulloblastoma, however comprehensive analysis of SUFU, BTRC and MXI1 indicates they are unlikely to represent major targets of these allelic losses. MXI1 mutation appears to play a role in the pathogenesis of a small subset of cases, and suggests an alternative mechanism to MYC amplification for disruption of the MYC/MAD/MAX network in medulloblastoma.
Scott
Deborah K
DK
Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
Straughton
Debbie
D
Cole
Michael
M
Bailey
Simon
S
Ellison
David W
DW
Clifford
Steven C
SC
D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10; D004252:DNA Mutational Analysis; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000209:etiology / Q000235:genetics*; D020161:Physical Chromosome Mapping; D012097:Repressor Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C471644:BTRC protein, human; C079440:MXI1 protein, human; C490764:SUFU protein, human