Pediatric Chordoma: A Tale of Two Genomes
Katrina O'Halloran1, Hesamedin Hakimjavadi2, Moiz Bootwalla2
1Department of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California.
Molecular Cancer Research : MCR
|May 1, 2024
Summary
Genomic analysis reveals mitochondrial DNA mutations and rare ARID1B gene alterations in pediatric chordoma. These findings suggest a significant role for germline ARID1B indels and mtDNA aberrations in chordoma development, particularly in young patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Chordoma genomic alterations are largely unknown, except for SMARCB1 loss in poorly differentiated types.
- Known genetic loci include TBXT duplication and rs2305089 polymorphism at 6q27.
- Comprehensive genomic analysis of pediatric chordoma's nuclear and mitochondrial DNA is lacking.
Purpose of the Study:
- To conduct a comprehensive genomic analysis of pediatric chordoma.
- To compare pediatric chordoma genomic findings with adult skull base chordoma.
- To investigate the role of nuclear and mitochondrial genome alterations in chordoma genesis.
Main Methods:
- Whole exome sequencing (WES) and mtDNA genome sequencing on 29 pediatric chordomas.
- Comparison with whole-genome sequencing data from 80 adult chordomas.
- Analysis of nuclear genome for germline indels and mtDNA for mutations.
Main Results:
- Somatic mtDNA mutations were significantly enriched in NADH complex genes in both pediatric (81%) and adult chordomas.
- Progressive increase in heteroplasmy of nonsynonymous mtDNA mutations observed in patients with multiple tumors.
- Rare likely germline in-frame indels in ARID1B (SWI/SNF complex) found in 22% of pediatric and 5% of adult chordomas, significantly higher than controls.
Conclusions:
- Germline ARID1B indels and mitochondrial DNA aberrations are implicated in chordoma genesis.
- These genetic factors appear particularly important in the development of pediatric chordoma.
- The study highlights novel genetic insights into chordoma, especially in pediatric cases.
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