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

Germ Cells Germ-Line Mutation Humans Male Neoplasm Recurrence, Local / genetics Phosphatidylinositol 3-Kinases / genetics Prostatectomy Prostatic Neoplasms / surgery Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins p21(ras) / genetics TOR Serine-Threonine Kinases
Biochemical recurrence Germline variants Pan Prostate Cancer Group Prostate cancer

Journal

European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719

Informations de publication

Date de publication:
08 2022
Historique:
received: 22 11 2021
revised: 06 04 2022
accepted: 10 05 2022
pubmed: 7 6 2022
medline: 14 7 2022
entrez: 6 6 2022
Statut: ppublish

Résumé

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.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.eururo.2022.05.007 PMID: 35659150
pubmed: 35659150
pii: S0302-2838(22)02341-7
doi: 10.1016/j.eururo.2022.05.007
pii:
doi:

Substances chimiques

Proto-Oncogene Proteins c-akt EC 2.7.11.1
TOR Serine-Threonine Kinases EC 2.7.11.1
Proto-Oncogene Proteins p21(ras) EC 3.6.5.2

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

201-211

Subventions

Organisme : Department of Health
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5047/A14835
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C14303/A17197
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C35696/A23187
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P50 CA211024
Pays : United States

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Auteurs

Daniel Burns (D)

The Institute of Cancer Research, London, UK.

Ezequiel Anokian (E)

The Institute of Cancer Research, London, UK.

Edward J Saunders (EJ)

The Institute of Cancer Research, London, UK.

Robert G Bristow (RG)

Manchester Cancer Research Centre and CRUK Manchester Institute, The University of Manchester, Manchester, UK.

Michael Fraser (M)

Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Jüri Reimand (J)

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.

Thorsten Schlomm (T)

Charité - Universitätsmedizin Berlin, Berlin, Germany.

Guido Sauter (G)

University Medical Centre Hamburg - Eppendorf, Hamburg, Germany.

Benedikt Brors (B)

German Cancer Research Center (DKFZ), Deutsches Krebsforschungszentrum, Heidelberg, Germany.

Jan Korbel (J)

European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.

Joachim Weischenfeldt (J)

Charité - Universitätsmedizin Berlin, Berlin, Germany; Biotech Research & Innovation Centre (BRIC) & Finsen Laboratory, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Sebastian M Waszak (SM)

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.

Niall M Corcoran (NM)

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.

Chol-Hee Jung (CH)

The University of Melbourne, Grattan Street, Parkville, Victoria, Australia.

Bernard J Pope (BJ)

Department of Surgery, The University of Melbourne, Grattan Street, Parkville, Victoria, Australia; Royal Melbourne Hospital, Melbourne, Parwille, Victoria, Australia.

Chris M Hovens (CM)

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.

Géraldine Cancel-Tassin (G)

CeRePP, Hopital Tenon, Paris, France; Sorbonne Universite, GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, Paris, France.

Olivier Cussenot (O)

CeRePP, Hopital Tenon, Paris, France; Sorbonne Universite, GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, Paris, France.

Massimo Loda (M)

Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Chris Sander (C)

cBio Center, Dana-Farber Cancer Institute, Boston, MA, USA.

Vanessa M Hayes (VM)

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.

Karina Dalsgaard Sorensen (K)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark.

Yong-Jie Lu (YJ)

Centre for Biomarker and Therapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK.

Freddie C Hamdy (FC)

Nuffield Department of Surgical Sciences University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.

Christopher S Foster (CS)

The Institute of Cancer Research, London, UK.

Vincent Gnanapragasam (V)

Department of Surgery, Division of Urology, University of Cambridge, Cambridge, UK.

Adam Butler (A)

Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.

Andy G Lynch (AG)

School of Medicine, University of St Andrews, St Andrews, Fife, UK; School of Mathematics & Statistics, St Andrews, Fife, UK.

Charlie E Massie (CE)

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.

Dan J Woodcock (DJ)

Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.

Colin S Cooper (CS)

Norwich Medical School, University of East Anglia, Norwich, UK.

David C Wedge (DC)

Manchester Cancer Research Centre, The University of Manchester, Manchester, UK.

Daniel S Brewer (DS)

Norwich Medical School, University of East Anglia, Norwich, UK; The Earlham Institute, Norwich Research Park, Norwich, UK.

Zsofia Kote-Jarai (Z)

The Institute of Cancer Research, London, UK. Electronic address: Zsofia.Kote-Jarai@icr.ac.uk.

Rosalind A Eeles (RA)

The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules germinales › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation germinale › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Rare Germline Variants Are Associated with...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Procédures de chirurgie opératoire › Procédures de chirurgie urogénitale › Procédures de chirurgie urologique › Procédures de chirurgie urologique masculine › Prostatectomie › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes p21(ras) › Rare Germline Variants Are Associated with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Rare Germline Variants Are Associated with...