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

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.; Martens, J. W. M.; Sleijfer, S.; Cuppen, E.; Zwart, W.; van de Werken, H. J. G.; Mehra, N.; Lolkema, M. P.

doi:10.1101/546051

bioRxiv · 10.1101/546051

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

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.·Martens, J. W. M.·Sleijfer, S.·Cuppen, E.·Zwart, W.·van de Werken, H. J. G.·Mehra, N.·Lolkema, M. P.

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Abstract

Here we present whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 castration-resistant prostate cancer patients. Using hierarchical unsupervised clustering based on genomic aberrations only, we defined eight different clusters. We detected four distinct and potentially clinically relevant genotypes harboring unique genomic features, including: 1) Microsatellite Instability; 2) Homologous Recombination Deficiency (HRD) with enriched genomic deletions and BRCA2 aberrations; 3) tandem duplication phenotype associated with biallelic CDK12 mutations; and 4) a subgroup enriched for chromothripsis events. Our data suggest that classifying patients using WGS characteristics may improve classification of HRD patients. Moreover, we confirmed that important regulators of AR-mediated signaling are located in non-coding regions. Using ChIP sequencing data, we showed that the amplified AR and MYC promoter regions contain open chromatin and bind AR, suggesting a role in AR mediated biology. Thus, high-resolution WGS may be used to improve patient stratification.

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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., Martens, J. W. M., Sleijfer, S., Cuppen, E., Zwart, W., van de Werken, H. J. G., Mehra, N., Lolkema, M. P.. 2019-02-11. The genomic landscape of metastatic castration-resistant prostate cancers using whole genome sequencing reveals multiple distinct genotypes with potential clinical impact. https://doi.org/10.1101/546051

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