EURURO Vol. 71 No. 5

Introduction

While over 1 111 700 men are diagnosed with prostate

cancer (PCa) each year worldwide, a much smaller number

(307 500) eventually die from this disease

[1] .

Understand-

ing the inherited factors contributing to the progression of

PCa to a lethal disease could have an important translational

impact on the detection, diagnosis, and prognosis of this

common cancer. Specifically, a currently unmet clinical

need is to be able to predict which men are more likely to

develop a lethal PCa versus an indolent one.

The past 10 yr have seen substantial progress in

elucidating molecular factors affecting PCa susceptibility

with the identification of over 100 common genetic variants

associated with an increased risk of PCa

[2]

. Although these

factors provide robust markers of PCa risk overall, they are

limited in distinguishing the risk for lethal versus indolent

PCa

[3,4]

One gene has emerged as a potentially specific driver of

more aggressive PCa. In 1997, Sigurdsson et al

[5]

described

the association of a deleterious founder mutation in

BRCA2

with aggressive PCa in Icelandic families. Subsequently,

multiple studies confirmed the link between PCa and

BRCA2

emphasizing

BRCA2

as a strong risk factor

[6–9]

. Castro et al

[2_TD$DIFF]

and others have described and characterized

BRCA2

as an

important prognostic factor for aggressive PCa

[10–19] ;

however, the mutation frequency was low and most

estimates suggested that

BRCA2

accounted for a very small

fraction of PCa (1–2%), even when early-onset family

history-positive cases were examined

[20–23]

. In a seminal

paper, Robinson et al

[24]

identified mutations in three DNA

repair genes,

BRCA1/2

, and

ATM

, at a surprisingly high rate in

men unselected for age at diagnosis or family history, but

rather for aggressive disease.

More recently, Pritchard et al

[25]

demonstrated an

elevated rate of mutations in a number of DNA repair genes

in men with metastatic PCa. Importantly, the combined

frequency of pathogenic mutations in a set of genes

including

BRCA1/2

and

ATM

was higher than that reported

in either the Exome Aggregation Consortium database of

53 000 unselected individuals or in the Cancer Genome

Atlas database of men with clinically localized PCa.

However, mixed racial populations and different sequenc-

ing technologies among study populations emphasize the

need for confirmation of these findings.

In this study, we directly compared germline pathogenic

mutations in

BRCA1/2

and

ATM

among lethal and indolent

(low risk localized) PCa patients from three racial groups

and assessed the effect mutational status on age at death in

a large case-case PCa cohort.

Patients and methods

2.1.

Study participants

This is a retrospective case-case study including 313 independent

patients with lethal PCa and 486 independent patients with low risk

localized PCa of European American, African American, and Chinese

ancestry. Study participants were ascertained from patients undergoing

PCa treatment in both the Brady Urological Institute and the Sidney

Kimmel Comprehensive Cancer Center of the Johns Hopkins Medical

Center, Baltimore, MD, USA (Hopkins), patients undergoing active

surveillance at the John and Carol Walter Center for Urological Health,

NorthShore University HealthSystem (NorthShore), as well as patients

treated for PCa in the Department Huashan Hospital, Fudan University,

Shanghai, China (Huashan). Lethal PCa in this study was defined as death

due to metastatic PCa (obtained by death certificates and review of the

patients’ medical records). Localized PCa were patients diagnosed with

low-risk disease, including PCa patients undergoing radical surgery with

pathological findings consistent with low-risk (pathological Gleason

score 6, organ confined; Hopkins), PCa patients underwent active

surveillance (NorthShore), and PCa patients met criteria of active

surveillance (Huashan).

Clinical and demographic information of these patients, including

age, race, prostate-specific antigen (PSA), Gleason score at time of PCa

diagnosis, and years from diagnosis to death are summarized in

Table 1

. The Institutional Review Board at Johns Hopkins Medical

Center, NorthShore University HealthSystem, and Huashan Hospital

approved this study and when required, written informed consent was

obtained from all study participants.

2.2.

Sequencing of germline DNA

Whole-exome sequencing (WES) was performed on germline DNA

derived from the blood of 129 lethal PCa patients at the PerkinElmer

Next-generation Sequencing Service Laboratory. The Agilent SureSelect

Human All Exon V5 was used to capture and enrich exome. Enriched

libraries were sequenced using an Illumina HiSeq 2500 system. The

mean sequencing depth of coverage was 71 . In addition, a customized

next-generation sequencing panel targeting 222 cancer related genes

was used to sequence the germline DNA of the remaining lethal PCa

patients and all the indolent PCa patients. Probes for capturing exon

regions (including 10 flanking intronic sequence) in these genes were

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,

= 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,

= 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.

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