Accumulation of copy number alterations and clinical progression across advanced prostate cancer
Abstract Background 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. M...
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-022-01080-4 |
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| author | Emily Grist Stefanie Friedrich Christopher Brawley Larissa Mendes Marina Parry Adnan Ali Aine Haran Alex Hoyle Claire Gilson Sharanpreet Lall Leila Zakka Carla Bautista Alex Landless Karolina Nowakowska Anna Wingate Daniel Wetterskog A. M. Mahedi Hasan Nafisah B. Akato Malissa Richmond Sofeya Ishaq Nik Matthews Anis A. Hamid Christopher J. Sweeney Matthew R. Sydes Daniel M. Berney Stefano Lise STAMPEDE investigators Mahesh K. B. Parmar Noel W. Clarke Nicholas D. James Paolo Cremaschi Louise C. Brown Gerhardt Attard |
| author_facet | Emily Grist Stefanie Friedrich Christopher Brawley Larissa Mendes Marina Parry Adnan Ali Aine Haran Alex Hoyle Claire Gilson Sharanpreet Lall Leila Zakka Carla Bautista Alex Landless Karolina Nowakowska Anna Wingate Daniel Wetterskog A. M. Mahedi Hasan Nafisah B. Akato Malissa Richmond Sofeya Ishaq Nik Matthews Anis A. Hamid Christopher J. Sweeney Matthew R. Sydes Daniel M. Berney Stefano Lise STAMPEDE investigators Mahesh K. B. Parmar Noel W. Clarke Nicholas D. James Paolo Cremaschi Louise C. Brown Gerhardt Attard |
| author_sort | Emily Grist |
| collection | DOAJ |
| description | Abstract Background 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 NCT00268476 , registered on December 22, 2005. EudraCT 2004-000193-31 , registered on October 4, 2004. |
| first_indexed | 2024-04-12T05:18:01Z |
| format | Article |
| id | doaj.art-506e0f56118040028d430cc8873797f0 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-12T05:18:01Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-506e0f56118040028d430cc8873797f02022-12-22T03:46:35ZengBMCGenome Medicine1756-994X2022-09-0114111510.1186/s13073-022-01080-4Accumulation of copy number alterations and clinical progression across advanced prostate cancerEmily Grist0Stefanie Friedrich1Christopher Brawley2Larissa Mendes3Marina Parry4Adnan Ali5Aine Haran6Alex Hoyle7Claire Gilson8Sharanpreet Lall9Leila Zakka10Carla Bautista11Alex Landless12Karolina Nowakowska13Anna Wingate14Daniel Wetterskog15A. M. Mahedi Hasan16Nafisah B. Akato17Malissa Richmond18Sofeya Ishaq19Nik Matthews20Anis A. Hamid21Christopher J. Sweeney22Matthew R. Sydes23Daniel M. Berney24Stefano Lise25STAMPEDE investigatorsMahesh K. B. Parmar26Noel W. Clarke27Nicholas D. James28Paolo Cremaschi29Louise C. Brown30Gerhardt Attard31Cancer Institute, University College LondonCancer Institute, University College LondonMRC Clinical Trials Unit at University College LondonCancer Institute, University College LondonCancer Institute, University College LondonGU Cancer Research/FASTMAN Group, Manchester Cancer InstituteThe Christie and Salford Royal NHS Foundation TrustsThe Christie and Salford Royal NHS Foundation TrustsMRC Clinical Trials Unit at University College LondonCancer Institute, University College LondonCancer Institute, University College LondonCancer Institute, University College LondonCancer Institute, University College LondonCancer Institute, University College LondonCancer Institute, University College LondonCancer Institute, University College LondonCancer Institute, University College LondonMRC Clinical Trials Unit at University College LondonMRC Clinical Trials Unit at University College LondonMRC Clinical Trials Unit at University College LondonThe Institute of Cancer ResearchDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteMRC Clinical Trials Unit at University College LondonBarts Cancer Institute, Queen Mary University of LondonCancer Institute, University College LondonMRC Clinical Trials Unit at University College LondonGU Cancer Research/FASTMAN Group, Manchester Cancer InstituteThe Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer ResearchCancer Institute, University College LondonMRC Clinical Trials Unit at University College LondonCancer Institute, University College LondonAbstract Background 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 NCT00268476 , registered on December 22, 2005. EudraCT 2004-000193-31 , registered on October 4, 2004.https://doi.org/10.1186/s13073-022-01080-4Advanced prostate cancerGenomic biomarkersCopy number alterationSTAMPEDE trial |
| spellingShingle | Emily Grist Stefanie Friedrich Christopher Brawley Larissa Mendes Marina Parry Adnan Ali Aine Haran Alex Hoyle Claire Gilson Sharanpreet Lall Leila Zakka Carla Bautista Alex Landless Karolina Nowakowska Anna Wingate Daniel Wetterskog A. M. Mahedi Hasan Nafisah B. Akato Malissa Richmond Sofeya Ishaq Nik Matthews Anis A. Hamid Christopher J. Sweeney Matthew R. Sydes Daniel M. Berney Stefano Lise STAMPEDE investigators Mahesh K. B. Parmar Noel W. Clarke Nicholas D. James Paolo Cremaschi Louise C. Brown Gerhardt Attard Accumulation of copy number alterations and clinical progression across advanced prostate cancer Genome Medicine Advanced prostate cancer Genomic biomarkers Copy number alteration STAMPEDE trial |
| title | Accumulation of copy number alterations and clinical progression across advanced prostate cancer |
| title_full | Accumulation of copy number alterations and clinical progression across advanced prostate cancer |
| title_fullStr | Accumulation of copy number alterations and clinical progression across advanced prostate cancer |
| title_full_unstemmed | Accumulation of copy number alterations and clinical progression across advanced prostate cancer |
| title_short | Accumulation of copy number alterations and clinical progression across advanced prostate cancer |
| title_sort | accumulation of copy number alterations and clinical progression across advanced prostate cancer |
| topic | Advanced prostate cancer Genomic biomarkers Copy number alteration STAMPEDE trial |
| url | https://doi.org/10.1186/s13073-022-01080-4 |
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