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

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

doi:10.1038/s41467-021-25469-8

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

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

Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Article number	5172
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25469-8
State	Published - Dec 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-25469-8

Cite this

Maclachlan, K. H., Rustad, E. H., Derkach, A., Zheng-Lin, B., Yellapantula, V., Diamond, B., Hultcrantz, M., Ziccheddu, B., Boyle, E. M., Blaney, P., Bolli, N., Zhang, Y., Dogan, A., Lesokhin, A. M., Morgan, G. J., Landgren, O., & Maura, F. (2021). Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma. Nature communications, 12(1), [5172]. https://doi.org/10.1038/s41467-021-25469-8

Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma. / Maclachlan, Kylee H.; Rustad, Even H.; Derkach, Andriy; Zheng-Lin, Binbin; Yellapantula, Venkata; Diamond, Benjamin; Hultcrantz, Malin; Ziccheddu, Bachisio; Boyle, Eileen M.; Blaney, Patrick; Bolli, Niccolò; Zhang, Yanming; Dogan, Ahmet; Lesokhin, Alexander M.; Morgan, Gareth J.; Landgren, Ola; Maura, Francesco.

In: Nature communications, Vol. 12, No. 1, 5172, 12.2021.

Research output: Contribution to journal › Article › peer-review

Maclachlan, KH, Rustad, EH, Derkach, A, Zheng-Lin, B, Yellapantula, V, Diamond, B, Hultcrantz, M, Ziccheddu, B, Boyle, EM, Blaney, P, Bolli, N, Zhang, Y, Dogan, A, Lesokhin, AM, Morgan, GJ, Landgren, O & Maura, F 2021, 'Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma', Nature communications, vol. 12, no. 1, 5172. https://doi.org/10.1038/s41467-021-25469-8

Maclachlan, Kylee H. ; Rustad, Even H. ; Derkach, Andriy ; Zheng-Lin, Binbin ; Yellapantula, Venkata ; Diamond, Benjamin ; Hultcrantz, Malin ; Ziccheddu, Bachisio ; Boyle, Eileen M. ; Blaney, Patrick ; Bolli, Niccolò ; Zhang, Yanming ; Dogan, Ahmet ; Lesokhin, Alexander M. ; Morgan, Gareth J. ; Landgren, Ola ; Maura, Francesco. / Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma. In: Nature communications. 2021 ; Vol. 12, No. 1.

@article{e6ca1d76630e4a82be199fa570de9190,

title = "Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma",

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.",

author = "Maclachlan, {Kylee H.} and Rustad, {Even H.} and Andriy Derkach and Binbin Zheng-Lin and Venkata Yellapantula and Benjamin Diamond and Malin Hultcrantz and Bachisio Ziccheddu and Boyle, {Eileen M.} and Patrick Blaney and Niccol{\`o} Bolli and Yanming Zhang and Ahmet Dogan and Lesokhin, {Alexander M.} and Morgan, {Gareth J.} and Ola Landgren and Francesco Maura",

note = "Funding Information: This work is supported by the Multiple Myeloma Research Foundation (MMRF), the Perelman Family Foundation, the Riney Family Multiple Myeloma Research Program Fund, a Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748), and by a Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139). F.M. is supported by the American Society of Hematology, the International Myeloma Foundation, and The Society of Memorial Sloan Kettering Cancer Center. K.H.M. is supported by the Haematology Society of Australia and New Zealand, the Royal College of Pathologists of Australasia, the Royal Australasian College of Physicians, the Snowdome Foundation, and the Multiple Myeloma Research Foundation. G.J.M. is supported by The Leukemia Lymphoma Society. N.B. is supported by the European Research Council under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement No. 817997) Funding Information: O.L. has received research funding from: National Institutes of Health (NIH), National Cancer Institute (NCI), U.S. Food and Drug Administration (FDA), Multiple Myeloma Research Foundation (MMRF), International Myeloma Foundation (IMF), Leukemia and Lymphoma Society (LLS), Perelman Family Foundation, Rising Tide Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; Honoraria/ ad boards: Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; and serves on Independent Data Monitoring Committees (IDMCs) for clinical trials lead by Takeda, Merck, Janssen, Theradex. All other authors have no conflicts of interest to declare. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-25469-8",

language = "English (US)",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma

AU - Maclachlan, Kylee H.

AU - Rustad, Even H.

AU - Derkach, Andriy

AU - Zheng-Lin, Binbin

AU - Yellapantula, Venkata

AU - Diamond, Benjamin

AU - Hultcrantz, Malin

AU - Ziccheddu, Bachisio

AU - Boyle, Eileen M.

AU - Blaney, Patrick

AU - Bolli, Niccolò

AU - Zhang, Yanming

AU - Dogan, Ahmet

AU - Lesokhin, Alexander M.

AU - Morgan, Gareth J.

AU - Landgren, Ola

AU - Maura, Francesco

N1 - Funding Information: This work is supported by the Multiple Myeloma Research Foundation (MMRF), the Perelman Family Foundation, the Riney Family Multiple Myeloma Research Program Fund, a Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748), and by a Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139). F.M. is supported by the American Society of Hematology, the International Myeloma Foundation, and The Society of Memorial Sloan Kettering Cancer Center. K.H.M. is supported by the Haematology Society of Australia and New Zealand, the Royal College of Pathologists of Australasia, the Royal Australasian College of Physicians, the Snowdome Foundation, and the Multiple Myeloma Research Foundation. G.J.M. is supported by The Leukemia Lymphoma Society. N.B. is supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 817997) Funding Information: O.L. has received research funding from: National Institutes of Health (NIH), National Cancer Institute (NCI), U.S. Food and Drug Administration (FDA), Multiple Myeloma Research Foundation (MMRF), International Myeloma Foundation (IMF), Leukemia and Lymphoma Society (LLS), Perelman Family Foundation, Rising Tide Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; Honoraria/ ad boards: Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; and serves on Independent Data Monitoring Committees (IDMCs) for clinical trials lead by Takeda, Merck, Janssen, Theradex. All other authors have no conflicts of interest to declare. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85113739214&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85113739214&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-25469-8

DO - 10.1038/s41467-021-25469-8

M3 - Article

C2 - 34453055

AN - SCOPUS:85113739214

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5172

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this