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

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

doi:10.1038/s41467-021-21026-5

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.

Highlights

APOBEC signatures (SBS2 and SBS13) were only present in the TM sample, while absent in R and LM samples, which is consistent with results from a recent study reporting that APOBEC mutagenesis could generate mutations late in the evolution of metastatic disease in thoracic tumors[27]. In this genomic analysis of skull-base chordoma, we described a comprehensive genomic landscape of this rare cancer and identified several genomic features that were associated with disease progression and outcomes
Given the role of PBRM1 and SETD2 in chromatin remodeling, our data suggest that epigenetic dysregulation may play an important role in chordoma development
Previous Pan-cancer analysis found that significant focal Somatic copy number alteration (SCNA) regions without known cancer genes were enriched with genes involved in epigenetic regulation[29]

Summary

Introduction

To characterize the potential driver events for skull-base chordoma, we combined five patients with PBRM1 mutations and five patients with SVs involving PBRM1 (Fig. 4), which were validated by targeted sequencing. We identified candidate driver events (PBRM1+, SETD2+, CDKN2A/B+, TBXT/LYST+) in 33.75% (27 out of 80) of the skull-base chordoma patients we sequenced. The remaining tumors might be caused by nonsynonymous mutations or SCNAs/SVs in known cancer driver genes (observed in 8% patients, Fig. 2) or other driver genes/mechanisms for which statistical power was too low to detect in this study.

Results

Conclusion