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

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, Lisa Mirabello, Dilys M. Parry, Yixuan Zhai, Mingxuan Li, Jiang Du, Junmei Wang, Shuheng Zhang, Qian Liu, Peng Zhao, Songbai Gui, Alisa M. Goldstein, Yazhuo Zhang () and Xiaohong R. Yang
Additional contact information
Jiwei Bai: Capital Medical University
Jianxin Shi: National Cancer Institute, NIH, DHHS
Chuzhong Li: Capital Medical University
Shuai Wang: Capital Medical University
Tongwu Zhang: National Cancer Institute, NIH, DHHS
Xing Hua: National Cancer Institute, NIH, DHHS
Bin Zhu: National Cancer Institute, NIH, DHHS
Hela Koka: National Cancer Institute, NIH, DHHS
Ho-Hsiang Wu: National Cancer Institute, NIH, DHHS
Lei Song: National Cancer Institute, NIH, DHHS
Difei Wang: National Cancer Institute, NIH, DHHS
Mingyi Wang: National Cancer Institute, NIH, DHHS
Weiyin Zhou: National Cancer Institute, NIH, DHHS
Bari J. Ballew: National Cancer Institute, NIH, DHHS
Bin Zhu: National Cancer Institute, NIH, DHHS
Belynda Hicks: National Cancer Institute, NIH, DHHS
Lisa Mirabello: National Cancer Institute, NIH, DHHS
Dilys M. Parry: National Cancer Institute, NIH, DHHS
Yixuan Zhai: Capital Medical University
Mingxuan Li: Capital Medical University
Jiang Du: Capital Medical University
Junmei Wang: Capital Medical University
Shuheng Zhang: Capital Medical University
Qian Liu: Capital Medical University
Peng Zhao: Capital Medical University
Songbai Gui: Capital Medical University
Alisa M. Goldstein: National Cancer Institute, NIH, DHHS
Yazhuo Zhang: Capital Medical University
Xiaohong R. Yang: National Cancer Institute, NIH, DHHS

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21026-5

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