Pediatric Chordoma: A Tale of Two Genomes

Abstract

Little is known about 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 WES and mtDNA genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole-genome sequencing datasets of 80 adult patients with skull base chordoma. In the pediatric chordoma cohort, 81% of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared with 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 nonsynonymous 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 in 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 seem important for chordoma genesis, especially in pediatric chordoma.

Figure 1.

Oncoplot displaying non-synonymous heteroplasmic mtDNA variants in the pediatric chordoma cohort. Mitochondrial variants are color coded based on VEP variant classifications. Dot size corresponds to variant allele frequency. The right side displays the percentage of samples in which each variant is observed. The number of variants per sample is shown at the bottom.

Figure 2.

Oncoplot displaying heteroplasmic non-synonymous mtDNA variants in the skull base chordoma cohort from Bai et al.

Figure 3.. Variation in Mitochondrial DNA Allele Frequencies Across Multiple Samples per Patient.

Lines connect identical variants found in different samples from the same patient, illustrating the dynamic nature of variant frequencies over time or across conditions. Dots denote unique variants present in only one sample per patient. Color indicates the mitochondrial gene affected. For selected variants, line labels provide variant IDs. Panel A: missense variants, Panel B: synonymous variants. strike signifies a statistically significant difference (p < 0.05) in VAFs. Statistical method: One-Way ANOVA, pairwise comparison; Pairwise comparison: Games-Howell post-hoc test; p.value adjustment for multiple comparisons: Holm–Bonferroni method.

Figure 4.

Oncoplot of recurrently mutated nuclear genes in the pediatric chordoma cohort. Variants are color coded based on VEP variant classifications. Dot size corresponds to variant allele frequency. The right side displays orange bars indicating the percentage of samples in which each variant is observed. The number of variants per sample is shown at the bottom. Patient age and tumor source (primary or recurrent) are indicated at the bottom.

Figure 5.

ARID1B variants in matched tumor and germline samples in the skull base chordoma cohort. Variants are color coded based on VEP variant classifications. Dot size corresponds to variant allele frequency.