Accumulation of copy number alterations and clinical progression across advanced prostate cancer

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dc.contributor.authorGrist, E.
dc.contributor.authorFriedrich, S.
dc.contributor.authorBrawley, C.
dc.contributor.authorMendes, L.
dc.contributor.authorParry, M.
dc.contributor.authorAli, A.
dc.contributor.authorHaran, A.
dc.contributor.authorHoyle, A.
dc.contributor.authorGilson, C.
dc.contributor.authorLall, S.
dc.contributor.authorZakka, L.
dc.contributor.authorBautista, C.
dc.contributor.authorLandless, A.
dc.contributor.authorNowakowska, K.
dc.contributor.authorWingate, A.
dc.contributor.authorWetterskog, D.
dc.contributor.authorHasan, A.M.M.
dc.contributor.authorAkato, N.B.
dc.contributor.authorRichmond, M.
dc.contributor.authorIshaq, S.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractBackground: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10− 6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes. Trial registration: ClinicalTrials.gov NCT00 268476, registered on December 22, 2005. EudraCT 2004- 000193- 31, registered on October 4, 2004.
dc.description.statementofresponsibilityEmily Grist ... Christopher J. Sweeney ... et al.
dc.identifier.citationGenome Medicine, 2022; 14(1):102-1-102-15
dc.identifier.doi10.1186/s13073-022-01080-4
dc.identifier.issn1756-994X
dc.identifier.issn1756-994X
dc.identifier.orcidSweeney, C.J. [0000-0002-0398-6018]
dc.identifier.urihttps://hdl.handle.net/2440/146098
dc.language.isoen
dc.publisherBMC
dc.rights© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
dc.source.urihttps://doi.org/10.1186/s13073-022-01080-4
dc.subjectAdvanced prostate cancer; Genomic biomarkers; Copy number alteration; STAMPEDE trial
dc.subject.meshHumans
dc.subject.meshProstatic Neoplasms
dc.subject.meshDisease Progression
dc.subject.meshAndrogen Antagonists
dc.subject.meshProspective Studies
dc.subject.meshMale
dc.subject.meshDNA Copy Number Variations
dc.titleAccumulation of copy number alterations and clinical progression across advanced prostate cancer
dc.typeJournal article
pubs.publication-statusPublished

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