Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study
European Urology, Volume 82, No. 2, Year 2022
Notification
URL copied to clipboard!
Description
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. © 2022 The Author(s)
Authors & Co-Authors
Saunders, Edward J.
United Kingdom, London
The Institute of Cancer Research
Schlomm, Thorsten
Germany, Berlin
Charité – Universitätsmedizin Berlin
Sauter, Guido
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Brors, Benedikt
Germany, Heidelberg
German Cancer Research Center
Korbel, Jan O.
Germany, Heidelberg
European Molecular Biology Laboratory Heidelberg
Waszak, Sebastian M.
Norway, Oslo
Oslo Universitetssykehus
United States, San Francisco
University of California, San Francisco
Corcoran, Niall M.
Australia, Melbourne
University of Melbourne
Australia, Melbourne
Royal Melbourne Hospital
Australia, Melbourne
Walter and Eliza Hall Institute of Medical Research
Pope, Bernard J.
Australia, Melbourne
University of Melbourne
Australia, Melbourne
Royal Melbourne Hospital
Hovens, Christopher M.
Australia, Melbourne
Walter and Eliza Hall Institute of Medical Research
Australia, Melbourne
University of Melbourne
Cancel-Tassin, Géraldine
France, Paris
Hôpital Tenon
Cussenot, Olivier
France, Paris
Hôpital Tenon
Loda, Massimo F.
United States, New York
Weill Cornell Medicine
Hayes, Vanessa M.
Australia, Sydney
Garvan Institute of Medical Research
Australia, Sydney
The University of Sydney
Sørensen, Karina Dalsgaard Dalsgaard
Denmark, Aarhus
Aarhus Universitetshospital
Lu, Yongjie
United Kingdom, London
Queen Mary University of London
Hamdy, Freddie C.
United Kingdom, Oxford
University of Oxford
Gnanapragasam, Vincent J.
United Kingdom, Cambridge
University of Cambridge
Butler, Adam P.
United Kingdom, Hinxton
Wellcome Sanger Institute
Lynch, Andy G.
United Kingdom, St Andrews
University of st Andrews
Wedge, David C.
Unknown Affiliation
Kóte-Jarai, Zsofia S.
United Kingdom, London
The Institute of Cancer Research
Eeles, Rosalind A.
United Kingdom, London
The Institute of Cancer Research
United Kingdom, London
The Royal Marsden Nhs Foundation Trust
Statistics
Citations: 1
Authors: 22
Affiliations: 30
Identifiers
Doi:
10.1016/j.eururo.2022.05.007
ISSN:
03022838
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Study Design
Cohort Study
Study Approach
Quantitative
Participants Gender
Male