Pediatric Chordoma: A Tale of Two Genomes

Abstract

Little is known regarding the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed whole exome and mitochondrial DNA (mtDNA) genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole genome sequencing datasets of 80 adult skull base chordoma patients. In the pediatric chordoma cohort, 81% percent of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared to the rest of the mtDNA genes (p=0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (p<0.0001). Furthermore, a progressive increase in heteroplasmy of non-synonymous mtDNA mutations was noted in patients with multiple tumors (p=0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that of the adult cohort (p=0.0236, Fisher’s exact test), but they were both significantly higher than that in the ethnicity-matched populations (p<5.9e-07 and p<0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations appear important for chordoma genesis, especially in pediatric chordoma.