학술논문
Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.
Document Type
Academic Journal
Author
Saunders EJ; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Dadaev T; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Brook MN; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Wakerell S; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Govindasami K; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Rageevakumar R; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Hussain N; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Osborne A; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Keating D; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Lophatananon A; Division of Population Health, University of Manchester, Manchester, UK.; Muir KR; Division of Population Health, University of Manchester, Manchester, UK.; Darst BF; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA; Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Conti DV; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.; Haiman CA; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.; Antoniou AC; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Eeles RA; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.; Kote-Jarai Z; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. Electronic address: Zsofia.Kote-Jarai@icr.ac.uk.
Source
Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101724904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2588-9311 (Electronic) Linking ISSN: 25889311 NLM ISO Abbreviation: Eur Urol Oncol Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes.
Objective: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS).
Design, Setting, and Participants: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples.
Outcome Measurements and Statistical Analysis: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival.
Results and Limitations: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16 ) than noncarriers.
Conclusions: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations.
Patient Summary: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.
(Copyright © 2024 The Institute of Cancer Research. Published by Elsevier B.V. All rights reserved.)
Objective: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS).
Design, Setting, and Participants: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples.
Outcome Measurements and Statistical Analysis: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival.
Results and Limitations: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10
Conclusions: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations.
Patient Summary: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.
(Copyright © 2024 The Institute of Cancer Research. Published by Elsevier B.V. All rights reserved.)