Copy number signatures predict chromothripsis and associate with poor clinical outcomes in patients with newly diagnosed multiple myeloma

Abstract

AbstractChromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study, we interrogate 752 NDMM patients using whole genome sequencing (WGS) to study the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC=0.90) and can be used to identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis was confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC=0.97) and an independent series of 34 NDMM (AUC=0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we were able to predict both the presence of chromothripsis (AUC=0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.