TY - JOUR
T1 - Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment
T2 - A Pan Prostate Cancer Group Study
AU - Burns, Daniel
AU - Anokian, Ezequiel
AU - Saunders, Edward J
AU - Bristow, Robert G
AU - Fraser, Michael
AU - Reimand, Jüri
AU - Schlomm, Thorsten
AU - Sauter, Guido
AU - Brors, Benedikt
AU - Korbel, Jan
AU - Weischenfeldt, Joachim
AU - Waszak, Sebastian M
AU - Corcoran, Niall M
AU - Jung, Chol-Hee
AU - Pope, Bernard J
AU - Hovens, Chris M
AU - Cancel-Tassin, Géraldine
AU - Cussenot, Olivier
AU - Loda, Massimo
AU - Sander, Chris
AU - Hayes, Vanessa M
AU - Dalsgaard Sorensen, Karina
AU - Lu, Yong-Jie
AU - Hamdy, Freddie C
AU - Foster, Christopher S
AU - Gnanapragasam, Vincent
AU - Butler, Adam
AU - Lynch, Andy G
AU - Massie, Charlie E
AU - Woodcock, Dan J
AU - Cooper, Colin S
AU - Wedge, David C
AU - Brewer, Daniel S
AU - Kote-Jarai, Zsofia
AU - Eeles, Rosalind A
AU - CR-UK/Prostate Cancer UK, ICGC, The PPCG
N1 - Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Germ Cells
KW - Germ-Line Mutation
KW - Humans
KW - Male
KW - Neoplasm Recurrence, Local/genetics
KW - Phosphatidylinositol 3-Kinases/genetics
KW - Prostatectomy
KW - Prostatic Neoplasms/surgery
KW - Proto-Oncogene Proteins c-akt/genetics
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - TOR Serine-Threonine Kinases
KW - Germline variants
KW - Biochemical recurrence
KW - Pan Prostate Cancer Group
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85132415133&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2022.05.007
DO - 10.1016/j.eururo.2022.05.007
M3 - Journal article
C2 - 35659150
VL - 82
SP - 201
EP - 211
JO - Open Access Journal of Urology
JF - Open Access Journal of Urology
SN - 0302-2838
IS - 2
ER -