Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment : a PPCG study
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.
Citation
Burns , D , Anokiana , E , Saunders , E J , Bristow , R G , Fraser , M , Reimand , J , Schlomm , T , Sauter , G , Brors , B , Korbeli , J , Weischenfeldt , J , Waszak , S M , Corcoran , N M , Jung , C-H , Pope , B J , Hovens , C M , Cancel-Tassin , G , Cussenot , O , Loda , M , Sander , C , Hayes , V M , Sorensen , K D , Lu , Y-J , Hamdy , F C , Foster , C S , Gnanapragasam , V , Butler , A , Lynch , A , Massie , C E , CR-UK/Prostate Cancer UK, ICGC, The PPCG , Woodcock , D J , Cooper , C S , Wedge , D C , Brewer , D S , Kote-Jarai , Z & Eeles , R 2022 , ' Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment : a PPCG study ' , European Urology , vol. 82 , no. 2 , pp. 201-211 . https://doi.org/10.1016/j.eururo.2022.05.007
Publication
European Urology
Status
Peer reviewed
ISSN
0302-2838Type
Journal article
Description
Funding: We acknowledge support from Cancer Research UK C5047/A14835/A22530/ A17528, C309/A11566, C368/A6743, A368/A7990, C14303/A17197 (Z.K.-J., S. Merson, N.C., S.E., D.L., T. Dadaev, M.A., E.B., J.B., G.A., P.W., B.A.-L., D.S.B., C.S.C., R.A.E.), the Dallaglio Foundation (CR-UK Prostate Cancer ICGC Project and Pan Prostate Cancer Group), PC-UK/Movember (Z.K.-J.), the NIHR support to The Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust (Z.K.-J., N.D., S. Merson, N.C., S.E., D.L., T. Dadaev, S. Thomas, M.A., E.B., C.F., 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., D.S.B., C.S.C., R.A.E.), 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: “Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)” (grant G0500966/75466) (D.E.N., V.G.), the Li Ka Shing Foundation (D.C.W., D.J.W.), Canadian Institutes of Health Research (CIHR) Project Grant (J.R.), 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 sub-theme). 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 (C.S.C., D.S.B.). P.W. is a Cancer Research Life Fellow. 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., G.A.). We would like to acknowledge The D. J Fielding Medical Research Trust for its support.Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.
Related items
Showing items related by title, author, creator and subject.
-
"Will it affect our chances of having children?" and feeling "like a ticking bomb" —the fertility concerns and fears of cancer progression and recurrence in cancer treatment decision-making among young women diagnosed with gynaecological or breast cancer
Sobota, Aleksandra; Ozakinci, Gozde (2021-06-02) - Journal articleObjective Cancer treatment decision making process is particularly fraught with challenges for young women because the treatment can affect their reproductive potential. Among many factors affecting the process, fears of ... -
A systematic review of the supportive care needs of people living with and beyond cancer of the colon and/or rectum
Kotronoulas, Grigorios; Papadopoulou, Constantina; Cunningham, Kathryn; Simpson, Mhairi; Maguire, Roma (2017-08) - Journal itemPurpose: Gaining a clear understanding of the health needs and concerns of people with cancer of the colon and/or rectum can help identify ways to offer a comprehensive care package. Our aim was to systematically assess ... -
Determinants of fertility issues experienced by young women diagnosed with breast or gynaecological cancer - a quantitative, cross-cultural study
Sobota, Aleksandra; Ozakinci, Gozde (2018-09-06) - Journal articleBackground. Although there is a recognition of the importance of fertility to young women with cancer, we do not know who is at risk of distress related to fertility issues following diagnosis. We investigated the determinants ...