Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study
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Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression. Design, setting, and participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset. Outcome measurements and statistical analysis: A total of 15, 822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling. Results and limitations: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset. Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. Patient summary: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | European Urology |
| Vol/bind | 82 |
| Udgave nummer | 2 |
| Sider (fra-til) | 201-211 |
| Antal sider | 11 |
| ISSN | 0302-2838 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Acknowledgements: The authors thank those men with prostate cancer and the subjects who have donated their time and their samples to the Cambridge, Oxford, The Institute of Cancer Research, Johns Hopkins and University of Tampere BioMediTech Biorepositories for this study. We also acknowledge support of the research staff in S4 who so carefully curated the samples and the follow-up data (J. Burge, M. Corcoran, A. George, and S. Stearn). We thank M. Stratton for discussions when setting up the CR-UK Prostate Cancer ICGC Project. We thank the National Institute for Health Research, Hutchison Whampoa Limited, University of Cambridge, and the Human Research Tissue Bank (Addenbrooke’s Hospital), which is supported by the NIHR Cambridge Biomedical Research Centre; the Core Facilities at the Cancer Research UK Cambridge Institute, Orchid and Cancer Research UK, D. Holland from the Infrastructure Management Team, and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. The validation results shown are based upon data generated by the TCGA Research Network.
Funding Information:
Funding/Support and role of the sponsor: We acknowledge support from Cancer Research UK C5047/A14835/A22530/ A17528, C309/A11566, C368/A6743, A368/A7990, and C14303/A17197 (Zsofia Kote-Jarai, S. Merson, Niall M. Corcoran, S.E., D.L., T. Dadaev, M.A., E.B., J.B., G.A., P.W., B.A.-L., Daniel S. Brewer, Colin S. Cooper, and Rosalind A. Eeles); the Dallaglio Foundation (CR-UK Prostate Cancer ICGC Project and Pan Prostate Cancer Group), PC-UK/Movember (Zsofia Kote-Jarai), the NIHR support to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust (Zsofia Kote-Jarai, N.D., S. Merson, Niall M. Corcoran, S.E., D.L., T. Dadaev, S. Thomas, M.A., E.B., Christopher S. Foster, N.L., D.N., V.K., N.A., P.K., C.O., D.C., A.T., E.M., E.R., T. Dudderidge, S. Hazell, J.B., G.A., P.W., B.A.-L., Daniel S. Brewer, Colin S. Cooper, and Rosalind A. Eeles), Cancer Research UK funding to the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust CRUK Centre, the National Cancer Research Institute (National Institute of Health Research (NIHR) Collaborative Study (grant G0500966/75466; D.E.N. and Vincent Gnanapragasam): “Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)”, the Li Ka Shing Foundation (David C. Wedge and Dan J. Woodcock), Canadian Institutes of Health Research (CIHR) Project Grant (Jüri Reimand), and the Academy of Finland and Cancer Society of Finland (G.S.B.). D.M.B. is supported by Orchid. C.V.’s academic time was supported by the NIHR Oxford Biomedical Research Centre (Molecular Diagnostics Theme/Multimodal Pathology subtheme). We also acknowledge support from the Bob Champion Cancer Trust, the Masonic Charitable Foundation successor to the Grand Charity, the King Family, and the Stephen Hargrave Trust (Colin S. Cooper and Daniel S. Brewer). We acknowledge core facilities provided by CRUK funding to the CRUK ICR Centre, the CRUK Cancer Therapeutics Unit, and support for canSAR C35696/A23187 (P.W. and G.A.). We would like to acknowledge the D.J. Fielding Medical Research Trust for its support. Support for analysis of the Australian samples was provided through the PRECEPT program grant, cofunded by Movember and the Australian Federal Government (PI Niall M. Corcoran) as well as NHMRC projects grants #10413 (CIs Chris M. Hovens, Niall M. Corcoran, and R.E.A.) and #1104010 (CIs Chris M. Hovens and Niall M. Corcoran). Bernard J. Pope was supported by a Victorian Health and Medical Research Fellowship from the Department of Health and Human Services in the State of Victoria. Niall M. Corcoran was supported by a David Bickart Clinician Researcher Fellowship from the Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, and more recently by a Movember – Distinguished Gentleman’s Ride Clinician Scientist Award through the Prostate Cancer Foundation of Australia’s Research Program. The French Prostate ICGC project was founded by Institut National de la Santé et de la Recherche Médicale (INSERM) and Institut National du Cancer (INCa), grant INSERM CV_2011/023 (C18), with additional support from LYric (grant INCa-4662). The PPCG project at Weill Cornell Medicine is supported by NCI P50CA211024, DoD PC160357, DoD PC180582, and the Prostate Cancer Foundation.
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© 2022 The Author(s)
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