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

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

doi:10.1016/j.eururo.2022.05.007

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

Eur Urol. 2022 Aug;82(2):201-211. doi: 10.1016/j.eururo.2022.05.007. Epub 2022 May 31.

Authors

Daniel Burns¹, Ezequiel Anokian¹, Edward J Saunders¹, Robert G Bristow², Michael Fraser³, Jüri Reimand⁴, Thorsten Schlomm⁵, Guido Sauter⁶, Benedikt Brors⁷, Jan Korbel⁸, Joachim Weischenfeldt⁹, Sebastian M Waszak¹⁰, Niall M Corcoran¹¹, Chol-Hee Jung¹², Bernard J Pope¹³, Chris M Hovens¹⁴, Géraldine Cancel-Tassin¹⁵, Olivier Cussenot¹⁵, Massimo Loda¹⁶, Chris Sander¹⁷, Vanessa M Hayes¹⁸, Karina Dalsgaard Sorensen¹⁹, Yong-Jie Lu²⁰, Freddie C Hamdy²¹, Christopher S Foster¹, Vincent Gnanapragasam²², Adam Butler²³, Andy G Lynch²⁴, Charlie E Massie²⁵; CR-UK/Prostate Cancer UK, ICGC, The PPCG²⁶; Dan J Woodcock²⁷, Colin S Cooper²⁸, David C Wedge²⁹, Daniel S Brewer³⁰, Zsofia Kote-Jarai³¹, Rosalind A Eeles³²

Affiliations

¹ The Institute of Cancer Research, London, UK.
² Manchester Cancer Research Centre and CRUK Manchester Institute, The University of Manchester, Manchester, UK.
³ Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁴ 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.
⁵ Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁶ University Medical Centre Hamburg - Eppendorf, Hamburg, Germany.
⁷ German Cancer Research Center (DKFZ), Deutsches Krebsforschungszentrum, Heidelberg, Germany.
⁸ European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
⁹ Charité - Universitätsmedizin Berlin, Berlin, Germany; Biotech Research & Innovation Centre (BRIC) & Finsen Laboratory, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
¹⁰ 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.
¹¹ 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.
¹² The University of Melbourne, Grattan Street, Parkville, Victoria, Australia.
¹³ Department of Surgery, The University of Melbourne, Grattan Street, Parkville, Victoria, Australia; Royal Melbourne Hospital, Melbourne, Parwille, Victoria, Australia.
¹⁴ 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.
¹⁵ CeRePP, Hopital Tenon, Paris, France; Sorbonne Universite, GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, Paris, France.
¹⁶ Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁷ cBio Center, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁸ 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.
¹⁹ Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark.
²⁰ Centre for Biomarker and Therapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK.
²¹ Nuffield Department of Surgical Sciences University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
²² Department of Surgery, Division of Urology, University of Cambridge, Cambridge, UK.
²³ Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
²⁴ School of Medicine, University of St Andrews, St Andrews, Fife, UK; School of Mathematics & Statistics, St Andrews, Fife, UK.
²⁵ CRUK Cambridge Institute, Hutchison MRC Research Centre, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
²⁶ CR-UK/Prostate Cancer UK, ICGC, The Pan Prostate Cancer Group, UK.
²⁷ Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
²⁸ Norwich Medical School, University of East Anglia, Norwich, UK.
²⁹ Manchester Cancer Research Centre, The University of Manchester, Manchester, UK.
³⁰ Norwich Medical School, University of East Anglia, Norwich, UK; The Earlham Institute, Norwich Research Park, Norwich, UK.
³¹ The Institute of Cancer Research, London, UK. Electronic address: Zsofia.Kote-Jarai@icr.ac.uk.
³² The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.

PMID: 35659150
DOI: 10.1016/j.eururo.2022.05.007

Abstract

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.

Keywords: Biochemical recurrence; Germline variants; Pan Prostate Cancer Group; Prostate cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Germ Cells
Germ-Line Mutation
Humans
Male
Neoplasm Recurrence, Local / genetics
Phosphatidylinositol 3-Kinases* / genetics
Prostatectomy
Prostatic Neoplasms* / surgery
Prostatic Neoplasms* / therapy
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins p21(ras) / genetics
TOR Serine-Threonine Kinases

Substances

Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding