Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma

Kylee H Maclachlan,Bachisio Ziccheddu,Alexander M Lesokhin,Niccolò Bolli,Even H Rustad,Yanming Zhang,Ahmet Dogan,Francesco Maura,Eileen M Boyle,Ola Landgren,Malin Hultcrantz,Patrick Blaney,Gareth J Morgan,Binbin Zheng-Lin,Andriy Derkach,Venkata Yellapantula,Benjamin Diamond

doi:10.1038/s41467-021-25469-8

Abstract

Chromothripsis 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 investigate 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 identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is 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 are 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.

Highlights

Chromothripsis is detectable in 20–30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor
To take account of the biology of MM, we introduced a few modifications to the original CN features described by Macintyre et al.:[18] (i) given the known poor quality mapping and copy number complexity related to class switch recombination and VDJ rearrangements, the immunoglobulin regions corresponding to IgH, IgL, and IgK were removed; (ii) considering both the low-coverage long-insert whole genome sequencing (WGS) limitation for calling subclonal copy number events and the less complex MM karyotype compared to solid cancers, fixed criteria for copy number status were introduced
We demonstrated a high prevalence of complex structural events such as chromothripsis in MM (24%)

Summary

Introduction

Chromothripsis 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 investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. The ability of CN signatures to predict the presence of chromothripsis is 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 be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. The total focal CN gains within the regions of chromothripsis is often lower than in solid organ cancer, there are fewer breakpoints attributable to chromothripsis, and in MM there is a lack of enrichment for double-minutes and other more catastrophic events such as typhonas[1,8]

Methods

Results

Conclusion