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Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study
- Source :
- 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 . https://doi.org/10.1016/j.eururo.2022.05.007, 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 . https://doi.org/10.1016/j.eururo.2022.05.007
- Publication Year :
- 2021
-
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 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.
- Subjects :
- Male
Prostatectomy
Phosphatidylinositol 3-Kinases/genetics
Prostate cancer
Pan Prostate Cancer Group
Prostatic Neoplasms/surgery
Urology
TOR Serine-Threonine Kinases
Prostatic Neoplasms
Germline variants
Proto-Oncogene Proteins c-akt/genetics
Biochemical recurrence
Proto-Oncogene Proteins p21(ras)/genetics
Proto-Oncogene Proteins p21(ras)
Phosphatidylinositol 3-Kinases
Germ Cells
Humans
Neoplasm Recurrence, Local/genetics
Neoplasm Recurrence, Local
Proto-Oncogene Proteins c-akt
Germ-Line Mutation
Subjects
Details
- ISSN :
- 18737560 and 03022838
- Volume :
- 82
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- European urology
- Accession number :
- edsair.doi.dedup.....2a655e5cd8544adff008a7eb0206fea3