The driver landscape of sporadic chordoma

Abstract

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

Fig. 1

Driver landscape of 104 chordomas. a For the discovery cohort, in every tumour (column), driver events are indicated by gene (row) and type of mutation (colour coded; refer to legend). For extension cases, the overall prevalence of driver events in each gene is indicated (colour coded by mutation class). b The LYST protein is depicted, indicating the position of truncating mutations in the discovery (red circles) and extension (red squares) samples. Functional domains are indicated in blue

Fig. 2

T duplications in 11 chordoma genomes. Coverage tracks: for each tumour, the coverage of the T locus is shown over a 2 Mb window (upper panel) and a 100 kb window (lower panel). X axis: genomic position. Y axis: coverage (unit: number of 5′ ends of fragments in a bin/(length of bin × reads for sample) × 3 × 10⁹). The error bars show the 95% confidence interval for the true mean coverage in each coverage bin. The colour coding of the error bars expresses the average mapping score in each bin (light = high; dark = low mapping score). Rearrangements are displayed as vertical black lines at the breakpoints connected by an upward arc for tandem duplications, a downward arc for deletions, and a straight line for inversions. BAF (B-allele frequency) track: the BAF tracks show the allele frequencies of heterozygous SNPs. Allele frequencies were plotted in a colour corresponding to their inferred parental chromosome, as determined by comparison to imputed haplotype blocks provided by the 1000 genomes project. X axis: genomic position. Y axis: B-allele frequency