title: Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.
abstract: Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk.
  
  
  
  To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death.
  
  
  
  A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes.
  
  
  
  Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively.
  
  
  
  The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed.
  
  
  
  Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time.
  
  
  
  Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China; Program for Isaacs Personalized Cancer Care, IL, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Na
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Misop
authors.initials: M
authors.lastname: Han
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yu
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Deke
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA.
authors.forename: Sameep
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Ewing
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Liti
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Kristian
authors.initials: K
authors.lastname: Novakovic
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Petkewicz
authors.affiliation: Department of Center for Molecular Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA.
authors.forename: Kamalakar
authors.initials: K
authors.lastname: Gulukota
authors.affiliation: Department of Center for Molecular Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Helseth
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Margo
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Humphries
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Wiley
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yishuo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China; Program for Isaacs Personalized Cancer Care, IL, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA.
authors.forename: Chi-Hsiung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Center for Molecular Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA.
authors.forename: Janardan
authors.initials: J
authors.lastname: Khandekar
authors.affiliation: Department of Medicine, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hulick
authors.affiliation: Department of Medicine, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Shevrin
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhoujun
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: H Ballentine
authors.initials: HB
authors.lastname: Carter
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Sam R
authors.initials: SR
authors.lastname: Denmeade
authors.affiliation: Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McGuire
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Walsh
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Helfand
authors.affiliation: Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Brendler
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: qiangd.urol@gmail.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China; Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China. Electronic address: jxu@northshore.org.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address: wisaacs@jhmi.edu.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
mesh_terms: D000367:Age Factors; D000368:Aged; D044466:Asian People / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D044465:White People / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA repair genes; Germline; Lethal prostate cancer; Mutation