Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR]=10.55, 95% confidence interval [CI]=2.81-39.64, p=0.001) and recurrence-free survival (HR=4.30, 95% CI=2.34-7.91, p=2.77 x 10(-6)). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma. Skull base chordomas are treated with surgery and chemotherapy but often recur due to incomplete resection, understanding the molecular underpinnings of the tumours may provide additional therapeutic strategies. Here, the authors carry out whole genome sequencing of 80 skull base chordoma tumours and identify the SWI/SNF component-PBRM1-as a frequently mutated gene.

Automated summary

Whole genome sequencing of 80 skull-base chordomas revealed PBRM1 mutations and homozygous deletions of the CDKN2A/2B locus as common events, associated with poor survival and high recurrence rates. Somatic copy number alterations play a vital role in chordoma initiation, showing highly concordant profiles between primary and recurrence/metastasis samples.