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Eur Urol. 2017 May;71(5):740-747. doi: 10.1016/j.eururo.2016.11.033. Epub 2016 Dec 15.

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.

Author information

1
Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China; Program for Isaacs Personalized Cancer Care, IL, USA.
2
Program for Isaacs Personalized Cancer Care, IL, USA; Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
3
Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Program for Isaacs Personalized Cancer Care, IL, USA; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
5
Program for Isaacs Personalized Cancer Care, IL, USA.
6
Department of Center for Molecular Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA.
7
Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
8
Department of Medicine, NorthShore University HealthSystem, Evanston, IL, USA.
9
Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
10
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
11
Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
12
Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: qiangd.urol@gmail.com.
13
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.
14
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.

Abstract

BACKGROUND:

Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk.

OBJECTIVE:

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.

DESIGN, SETTING, AND PARTICIPANTS:

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.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively.

RESULTS AND LIMITATIONS:

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.

CONCLUSIONS:

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.

PATIENT SUMMARY:

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.

KEYWORDS:

DNA repair genes; Germline; Lethal prostate cancer; Mutation

PMID:
27989354
PMCID:
PMC5535082
DOI:
10.1016/j.eururo.2016.11.033
[Indexed for MEDLINE]
Free PMC Article

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