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

Authors :
Burns, Daniel
Anokian, Ezequiel
Saunders, Edward J.
Bristow, Robert G.
Fraser, Michael
Reimand, Jüri
Schlomm, Thorsten
Sauter, Guido
Brors, Benedikt
Korbel, Jan
Weischenfeldt, Joachim
Waszak, Sebastian M.
Corcoran, Niall M.
Jung, Chol Hee
Pope, Bernard J.
Hovens, Chris M.
Cancel-Tassin, Géraldine
Cussenot, Olivier
Loda, Massimo
Sander, Chris
Hayes, Vanessa M.
Dalsgaard Sorensen, Karina
Lu, Yong Jie
Hamdy, Freddie C.
Foster, Christopher S.
Gnanapragasam, Vincent
Butler, Adam
Lynch, Andy G.
Massie, Charlie E.
Woodcock, Dan J.
Cooper, Colin S.
Wedge, David C.
Brewer, Daniel S.
Kote-Jarai, Zsofia
Eeles, Rosalind A.
Burns, Daniel
Anokian, Ezequiel
Saunders, Edward J.
Bristow, Robert G.
Fraser, Michael
Reimand, Jüri
Schlomm, Thorsten
Sauter, Guido
Brors, Benedikt
Korbel, Jan
Weischenfeldt, Joachim
Waszak, Sebastian M.
Corcoran, Niall M.
Jung, Chol Hee
Pope, Bernard J.
Hovens, Chris M.
Cancel-Tassin, Géraldine
Cussenot, Olivier
Loda, Massimo
Sander, Chris
Hayes, Vanessa M.
Dalsgaard Sorensen, Karina
Lu, Yong Jie
Hamdy, Freddie C.
Foster, Christopher S.
Gnanapragasam, Vincent
Butler, Adam
Lynch, Andy G.
Massie, Charlie E.
Woodcock, Dan J.
Cooper, Colin S.
Wedge, David C.
Brewer, Daniel S.
Kote-Jarai, Zsofia
Eeles, Rosalind A.
Source :
Burns , D , Anokian , E , Saunders , E J , Bristow , R G , Fraser , M , Reimand , J , Schlomm , T , Sauter , G , Brors , B , Korbel , 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 , Dalsgaard Sorensen , K , Lu , Y J , Hamdy , F C , Foster , C S , Gnanapragasam , V , Butler , A , Lynch , A G , Massie , C E , Woodcock , D J , Cooper , C S , Wedge , D C , Brewer , D S , Kote-Jarai , Z , Eeles , R A & CR-UK/Prostate Cancer UK, ICGC, The PPCG 2022 , ' Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment : A Pan Prostate Cancer Group Study ' , European Urology , vol. 82 , no. 2 , pp. 201-211 .
Publication Year :
2022

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

Details

Database :
OAIster
Journal :
Burns , D , Anokian , E , Saunders , E J , Bristow , R G , Fraser , M , Reimand , J , Schlomm , T , Sauter , G , Brors , B , Korbel , 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 , Dalsgaard Sorensen , K , Lu , Y J , Hamdy , F C , Foster , C S , Gnanapragasam , V , Butler , A , Lynch , A G , Massie , C E , Woodcock , D J , Cooper , C S , Wedge , D C , Brewer , D S , Kote-Jarai , Z , Eeles , R A & CR-UK/Prostate Cancer UK, ICGC, The PPCG 2022 , ' Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment : A Pan Prostate Cancer Group Study ' , European Urology , vol. 82 , no. 2 , pp. 201-211 .
Notes :
application/pdf, English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1349065531
Document Type :
Electronic Resource