The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact

Lisanne F. van Dessel; Job van Riet; Minke Smits; Yanyun Zhu; Paul Hamberg; Michiel S. van der Heijden; Andries M. Bergman; Inge M. van Oort; Ronald de Wit; Emile E. Voest; Neeltje Steeghs; Takafumi N. Yamaguchi; Julie Livingstone; Paul C. Boutros; John W.M. Martens; Stefan Sleijfer; Edwin Cuppen; Wilbert Zwart; Harmen J.G. van de Werken; Niven Mehra; Martijn P. Lolkema

doi:10.1038/s41467-019-13084-7

The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact

Lisanne F. van Dessel, Job van Riet, Minke Smits, Yanyun Zhu, Paul Hamberg, Michiel S. van der Heijden, Andries M. Bergman, Inge M. van Oort, Ronald de Wit, Emile E. Voest, Neeltje Steeghs, Takafumi N. Yamaguchi, Julie Livingstone, Paul C. Boutros, John W.M. Martens, Stefan Sleijfer, Edwin Cuppen, Wilbert Zwart, Harmen J.G. van de Werken, Niven MehraMartijn P. Lolkema (Corresponding author)

Chemical Biology

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

161 Citations (Scopus)

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12^−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12^−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Original language	English
Article number	5251
Number of pages	13
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13084-7
Publication status	Published - 1 Dec 2019

Funding

This publication and the underlying study have been made possible in parts by the data that the Hartwig Medical Foundation and the Center of Personalized Cancer Treatment (CPCT) have made available to the study. We would like to thank the local principal investigators of all contributing centers for their help with patient enrollment (listed in Supplementary Table 1). We would also like to thank Tesa M. Severson for her help with the computational analyses of the ChIP-seq data, Suzan Stelloo for providing ChIP-seq results on cell lines and Arne van Hoeck for providing the CHORD (HR-deficiency) prediction scores. We thank Dr. Joost van Rosmalen for his advises on the statistical analyses. In addition, we would like to thank the Barcode for Life foundation for making this research possible. Figure 1 was created with BioRender.com. This work was supported in parts by a KWF-Alpe d’HuZes project [NKI 2014-7080], a grant from Astellas Pharma [Lolkema/NL-72-RG-11] and a Johnson & Johnson grant [212082PCR3014]. This work was supported by the NIH/NCI under award number P30CA016042. H.J.G.v.D.W., J.v.R. and the Erasmus MC Cancer Computational Biology Center (CCBC) were financed through a grant from the Daniel den Hoed foundation.

Keywords

BRCA2 Protein/genetics
Bone Neoplasms/genetics
Chromatin Immunoprecipitation Sequencing
Cyclin-Dependent Kinases/genetics
DNA Copy Number Variations
Enhancer Elements, Genetic/genetics
Genotype
Humans
Liver Neoplasms/genetics
Lymph Nodes
Male
Microsatellite Instability
Neoplasm Metastasis
Oncogene Proteins, Fusion/genetics
Prostatic Neoplasms/genetics
Prostatic Neoplasms, Castration-Resistant/classification
Receptors, Androgen/genetics
Recombinational DNA Repair/genetics
Soft Tissue Neoplasms/genetics
Whole Genome Sequencing

UN SDGs

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

Access to Document

10.1038/s41467-019-13084-7

Cite this

van Dessel, L. F., van Riet, J., Smits, M., Zhu, Y., Hamberg, P., van der Heijden, M. S., Bergman, A. M., van Oort, I. M., de Wit, R., Voest, E. E., Steeghs, N., Yamaguchi, T. N., Livingstone, J., Boutros, P. C., Martens, J. W. M., Sleijfer, S., Cuppen, E., Zwart, W., van de Werken, H. J. G., ... Lolkema, M. P. (2019). The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact. Nature Communications, 10(1), Article 5251. https://doi.org/10.1038/s41467-019-13084-7

@article{a16e37b41ba54d6e894f78b4b730cdbf,

title = "The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact",

abstract = "Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.",

keywords = "BRCA2 Protein/genetics, Bone Neoplasms/genetics, Chromatin Immunoprecipitation Sequencing, Cyclin-Dependent Kinases/genetics, DNA Copy Number Variations, Enhancer Elements, Genetic/genetics, Genotype, Humans, Liver Neoplasms/genetics, Lymph Nodes, Male, Microsatellite Instability, Neoplasm Metastasis, Oncogene Proteins, Fusion/genetics, Prostatic Neoplasms/genetics, Prostatic Neoplasms, Castration-Resistant/classification, Receptors, Androgen/genetics, Recombinational DNA Repair/genetics, Soft Tissue Neoplasms/genetics, Whole Genome Sequencing",

author = "\{van Dessel\}, \{Lisanne F.\} and \{van Riet\}, Job and Minke Smits and Yanyun Zhu and Paul Hamberg and \{van der Heijden\}, \{Michiel S.\} and Bergman, \{Andries M.\} and \{van Oort\}, \{Inge M.\} and \{de Wit\}, Ronald and Voest, \{Emile E.\} and Neeltje Steeghs and Yamaguchi, \{Takafumi N.\} and Julie Livingstone and Boutros, \{Paul C.\} and Martens, \{John W.M.\} and Stefan Sleijfer and Edwin Cuppen and Wilbert Zwart and \{van de Werken\}, \{Harmen J.G.\} and Niven Mehra and Lolkema, \{Martijn P.\}",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13084-7",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

van Dessel, LF, van Riet, J, Smits, M, Zhu, Y, Hamberg, P, van der Heijden, MS, Bergman, AM, van Oort, IM, de Wit, R, Voest, EE, Steeghs, N, Yamaguchi, TN, Livingstone, J, Boutros, PC, Martens, JWM, Sleijfer, S, Cuppen, E, Zwart, W, van de Werken, HJG, Mehra, N & Lolkema, MP 2019, 'The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact', Nature Communications, vol. 10, no. 1, 5251. https://doi.org/10.1038/s41467-019-13084-7

TY - JOUR

T1 - The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact

AU - van Dessel, Lisanne F.

AU - van Riet, Job

AU - Smits, Minke

AU - Zhu, Yanyun

AU - Hamberg, Paul

AU - van der Heijden, Michiel S.

AU - Bergman, Andries M.

AU - van Oort, Inge M.

AU - de Wit, Ronald

AU - Voest, Emile E.

AU - Steeghs, Neeltje

AU - Yamaguchi, Takafumi N.

AU - Livingstone, Julie

AU - Boutros, Paul C.

AU - Martens, John W.M.

AU - Sleijfer, Stefan

AU - Cuppen, Edwin

AU - Zwart, Wilbert

AU - van de Werken, Harmen J.G.

AU - Mehra, Niven

AU - Lolkema, Martijn P.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

AB - Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

KW - BRCA2 Protein/genetics

KW - Bone Neoplasms/genetics

KW - Chromatin Immunoprecipitation Sequencing

KW - Cyclin-Dependent Kinases/genetics

KW - DNA Copy Number Variations

KW - Enhancer Elements, Genetic/genetics

KW - Genotype

KW - Humans

KW - Liver Neoplasms/genetics

KW - Lymph Nodes

KW - Male

KW - Microsatellite Instability

KW - Neoplasm Metastasis

KW - Oncogene Proteins, Fusion/genetics

KW - Prostatic Neoplasms/genetics

KW - Prostatic Neoplasms, Castration-Resistant/classification

KW - Receptors, Androgen/genetics

KW - Recombinational DNA Repair/genetics

KW - Soft Tissue Neoplasms/genetics

KW - Whole Genome Sequencing

UR - https://www.scopus.com/pages/publications/85075391947

U2 - 10.1038/s41467-019-13084-7

DO - 10.1038/s41467-019-13084-7

M3 - Article

C2 - 31748536

AN - SCOPUS:85075391947

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5251

ER -

The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact

Abstract

Funding

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this