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dc.contributor.authorBurns, D
dc.contributor.authorAnokian, E
dc.contributor.authorSaunders, EJ
dc.contributor.authorBristow, RG
dc.contributor.authorFraser, M
dc.contributor.authorReimand, J
dc.contributor.authorSchlomm, T
dc.contributor.authorSauter, G
dc.contributor.authorBrors, B
dc.contributor.authorKorbel, J
dc.contributor.authorWeischenfeldt, J
dc.contributor.authorWaszak, SM
dc.contributor.authorCorcoran, NM
dc.contributor.authorJung, C-H
dc.contributor.authorPope, BJ
dc.contributor.authorHovens, CM
dc.contributor.authorCancel-Tassin, G
dc.contributor.authorCussenot, O
dc.contributor.authorLoda, M
dc.contributor.authorSander, C
dc.contributor.authorHayes, VM
dc.contributor.authorDalsgaard Sorensen, K
dc.contributor.authorLu, Y-J
dc.contributor.authorHamdy, FC
dc.contributor.authorFoster, CS
dc.contributor.authorGnanapragasam, V
dc.contributor.authorButler, A
dc.contributor.authorLynch, AG
dc.contributor.authorMassie, CE
dc.contributor.authorCR-UK/Prostate Cancer UK, ICGC, The PPCG,
dc.contributor.authorWoodcock, DJ
dc.contributor.authorCooper, CS
dc.contributor.authorWedge, DC
dc.contributor.authorBrewer, DS
dc.contributor.authorKote-Jarai, Z
dc.contributor.authorEeles, RA
dc.identifier.citationEuropean Urology, 2022, 82 (2), pp. 201 - 211
dc.description.abstractBACKGROUND: 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.
dc.format.extent201 - 211
dc.relation.ispartofEuropean Urology
dc.subjectBiochemical recurrence
dc.subjectGermline variants
dc.subjectPan Prostate Cancer Group
dc.subjectProstate cancer
dc.subjectGerm Cells
dc.subjectGerm-Line Mutation
dc.subjectNeoplasm Recurrence, Local
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectProstatic Neoplasms
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectTOR Serine-Threonine Kinases
dc.titleRare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study.
dc.typeJournal Article
rioxxterms.typeJournal Article/Review
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Oncogenetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
dc.contributor.icrauthorSaunders, Edward
dc.contributor.icrauthorKote-Jarai, Zsofia
dc.contributor.icrauthorEeles, Rosalind
icr.provenanceDeposited by Mr Arek Surman on 2022-08-23. Deposit type is initial. No. of files: 1. Files: 1-s2.0-S0302283822023417-main.pdf

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