Show simple item record

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.coverage.spatialSwitzerland
dc.date.accessioned2022-08-23T10:09:10Z
dc.date.available2022-08-23T10:09:10Z
dc.date.issued2022-08-01
dc.identifierS0302-2838(22)02341-7
dc.identifier.citationEuropean Urology, 2022, 82 (2), pp. 201 - 211en_US
dc.identifier.issn0302-2838
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5307
dc.identifier.eissn1873-7560
dc.identifier.eissn1873-7560
dc.identifier.doi10.1016/j.eururo.2022.05.007
dc.identifier.doi10.1016/j.eururo.2022.05.007
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.formatPrint-Electronic
dc.format.extent201 - 211
dc.languageeng
dc.language.isoengen_US
dc.publisherElsevier BVen_US
dc.relation.ispartofEuropean Urology
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectBiochemical recurrence
dc.subjectGermline variants
dc.subjectPan Prostate Cancer Group
dc.subjectProstate cancer
dc.subjectGerm Cells
dc.subjectGerm-Line Mutation
dc.subjectHumans
dc.subjectMale
dc.subjectNeoplasm Recurrence, Local
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectProstatectomy
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.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-05-10
dc.date.updated2022-08-23T10:08:31Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1016/j.eururo.2022.05.007en_US
rioxxterms.licenseref.startdate2022-08-01
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35659150
pubs.issue2
pubs.organisational-group/ICR
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
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublished
pubs.volume82
icr.researchteamOncogeneticsen_US
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


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by-nc-nd/4.0/
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc-nd/4.0/