Genome-wide approach to identify second gene targets for malignant rhabdoid tumors using high-density oligonucleotide microarrays.
Bottom Line: Of the 20 specimens with deletions of 22q11.2, eight specimens showed uniparental disomy of the SMARCB1 locus with homozygous deletions or gene mutations.High-resolution analysis also disclosed the recurrent hemizygous/homozygous deletions of 7q35-q36.1, involving the CNTNAP2 locus in three specimens.Mutations analysis of CNTNAP2 showed a novel R157C missense mutation in a primary case, and methylation analysis showed recurrent hypermethylation of CNTNAP2 in three of nine cell lines.
Affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.Show MeSH
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Mentions: Although recurrent copy number changes other than 22q11.2 deletions were less frequent in MRT (Fig.1a), seven loci of gains and eight loci of losses were commonly detected in multiple samples (Table2). Importantly, some of the regions contained potential gene targets that were known to be associated with tumorigenesis of other cancers, such as CCNL1, POT1, CNTNAP2, and PRPTD (Table2).18,21,22 Detection of homozygous deletions was also of interest because they provide an important clue to pinpoint tumor suppressor loci. In fact, SMARCB1 was identified from homozygously deleted regions at 22q11.2.4 Of note, we found a homozygous deletion of the CNTNAP2 locus at 7q35–q36 in one specimen (STM-91-01), and another two cases (TTC-549 and MRT-7) showed a hemizygous deletion in this region (Fig.2a). The commonly deleted region of the CNTNAP2 locus was expanded in a 534-kb region (ch7:146,183,963-146,718-030) at 7q35–q36, and a homozygous deletion was involved in only exons 9–10 of CNTNAP2. Unfortunately, we were not able to completely exclude the possibility that this may represent copy number variations (CNV) rather than real homozygous/hemizygous deletions, because these homozygous deletions were found in established MRT cell lines. However, in our SNP array database, we did not find any CNV at the CNTNAP2 locus in 100 normal samples, but hemizygous/homozygous deletions were observed in two neuroblastoma cell lines (NB-16 and NB-19) (data not shown), suggesting that this deletions would be somatic events rather than CNV. Complete or incomplete losses of genetic materials at seven loci were confirmed by quantitative genomic PCR (Fig. S1).
Affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.