Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study.

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.

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.

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.

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.

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.

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.

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.

European urology. 2022 May 31 [Epub ahead of print]

Daniel Burns, Ezequiel Anokian, Edward J Saunders, Robert G Bristow, Michael Fraser, Jüri Reimand, Thorsten Schlomm, Guido Sauter, Benedikt Brors, Jan Korbel, Joachim Weischenfeldt, Sebastian M Waszak, Niall M Corcoran, Chol-Hee Jung, Bernard J Pope, Chris M Hovens, Géraldine Cancel-Tassin, Olivier Cussenot, Massimo Loda, Chris Sander, Vanessa M Hayes, Karina Dalsgaard Sorensen, Yong-Jie Lu, Freddie C Hamdy, Christopher S Foster, Vincent Gnanapragasam, Adam Butler, Andy G Lynch, Charlie E Massie, CR-UK/Prostate Cancer UK, ICGC, The PPCG , Dan J Woodcock, Colin S Cooper, David C Wedge, Daniel S Brewer, Zsofia Kote-Jarai, Rosalind A Eeles

The Institute of Cancer Research, London, UK., Manchester Cancer Research Centre and CRUK Manchester Institute, The University of Manchester, Manchester, UK., Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics & Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Charité - Universitätsmedizin Berlin, Berlin, Germany., University Medical Centre Hamburg - Eppendorf, Hamburg, Germany., German Cancer Research Center (DKFZ), Deutsches Krebsforschungszentrum, Heidelberg, Germany., European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Charité - Universitätsmedizin Berlin, Berlin, Germany; Biotech Research & Innovation Centre (BRIC) & Finsen Laboratory, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark., Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatric Research, Division of Pediatric and Adolescent Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway., Department of Surgery, The University of Melbourne, Grattan Street, Parkville, Victoria, Australia; Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia; Melbourne Bioinformatics, The University of Melbourne, Grattan Street, Victoria, Australia., The University of Melbourne, Grattan Street, Parkville, Victoria, Australia., Department of Surgery, The University of Melbourne, Grattan Street, Parkville, Victoria, Australia; Royal Melbourne Hospital, Melbourne, Parwille, Victoria, Australia., Melbourne Bioinformatics, The University of Melbourne, Grattan Street, Victoria, Australia; The University of Melbourne, Grattan Street, Parkville, Victoria, Australia; University of Melbourne Centre for Cancer Research, The Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia., CeRePP, Hopital Tenon, Paris, France; Sorbonne Universite, GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, Paris, France., Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., cBio Center, Dana-Farber Cancer Institute, Boston, MA, USA., Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia; School of Medical Sciences, University of Sydney, Charles Perkins Centre, Camperdown, NSW, Australia., Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark., Centre for Biomarker and Therapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK., Nuffield Department of Surgical Sciences University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK., Department of Surgery, Division of Urology, University of Cambridge, Cambridge, UK., Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK., School of Medicine, University of St Andrews, St Andrews, Fife, UK; School of Mathematics & Statistics, St Andrews, Fife, UK., CRUK Cambridge Institute, Hutchison MRC Research Centre, University of Cambridge, Li Ka Shing Centre, Cambridge, UK., CR-UK/Prostate Cancer UK, ICGC, The Pan Prostate Cancer Group, UK., Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK., Norwich Medical School, University of East Anglia, Norwich, UK., Manchester Cancer Research Centre, The University of Manchester, Manchester, UK., Norwich Medical School, University of East Anglia, Norwich, UK; The Earlham Institute, Norwich Research Park, Norwich, UK., The Institute of Cancer Research, London, UK. Electronic address: ., The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.

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