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Genome-wide approach to identify second gene targets for malignant rhabdoid tumors using high-density oligonucleotide
Junko Takita1, Yuyan Chen, Motohiro Kato
1Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Abstract:
Malignant rhabdoid tumor (MRT) is a rare and highly lethal cancer that mainly affects infants and young children. The majority of MRT are characterized by loss of function of SMARCB1 on chromosome 22q11.2. However, little is known about genetic changes other than SMARCB1 alterations that are responsible for the development and/or progression of MRT. To explore additional gene targets in MRT, we analyzed 21 MRT specimens (12 fresh tumors and 9 MRT-derived cell lines) using high-density single nucleotide polymorphism genotyping microarrays. Although MRT genomes are characterized by common 22q11.2 deletions, affecting the SMARCB1 locus with a frequency of 95.2% (20/21 specimens), other genetic changes have been less frequent. 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. These results demonstrated that CNTNAP2 is one of the additional gene targets, other than SMARCB1, in MRT.
Insights
Malignant rhabdoid tumor (MRT) is a rare childhood cancer. This study identified CNTNAP2 as a potential new gene target beyond SMARCB1, offering new avenues for MRT research and treatment.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Malignant rhabdoid tumor (MRT) is a rare, aggressive pediatric cancer.
- SMARCB1 gene alterations are the primary known drivers of MRT.
- Additional genetic factors contributing to MRT development remain largely unexplored.
Purpose of the Study:
- To identify novel genetic alterations beyond SMARCB1 in malignant rhabdoid tumors.
- To investigate the role of these additional genetic changes in MRT pathogenesis.
Main Methods:
- Analysis of 21 MRT specimens (12 tumors, 9 cell lines) using high-density SNP genotyping microarrays.
- High-resolution deletion analysis and mutation screening of candidate genes.
- Methylation analysis of identified loci in cell lines.
Main Results:
- Confirmed high frequency (95.2%) of SMARCB1 locus deletions (22q11.2).
- Identified recurrent hemizygous/homozygous deletions at 7q35-q36.1 involving the CNTNAP2 locus in 3/21 specimens.
- Detected a novel CNTNAP2 missense mutation (R157C) and recurrent hypermethylation in MRT samples.
Conclusions:
- CN জৈNAP2 is implicated as a novel, additional gene target in MRT development, alongside SMARCB1.
- These findings expand the understanding of MRT genetic landscape.
- CN জৈNAP2 alterations represent potential therapeutic targets for MRT.
