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

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-21026-5

2041-1723

Jiwei Bai, Jianxin Shi, Chuzhong Li, Shuai Wang, Tongwu Zhang, Xing Hua, Bin Zhu, Hela Koka, Ho‐Hsiang Wu, Lei Song, Difei Wang, Mingyi Wang, Weiyin Zhou, Bari J. Ballew, Bin Zhu, Belynda Hicks, Kari G. Rabe, Dilys M. Parry, Yixuan Zhai, Mingxuan Li, Jiang Du, Junmei Wang, Shuheng Zhang, Qian Liu, Peng Zhao, Songbai Gui, Alisa M. Goldstein, Yazhuo Zhang, Xiaohong Yang,

MicroRNA in disease regulation

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 × 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.