EURURO Vol. 71 No. 5

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this study simultaneously carried a mutation in ATM and
BRCA1 or -2.
Family history information was available in 669 patients
(417 with negative family history and 252 with positive
family history). The mutation carrier rates were similar in
patients with a negative family history (12/417, 2.9%) and
with a positive family history (8/252, 3.2%), p = 0.82.
In the entire cohort, mutation carrier status was not
significantly associated with age at diagnosis; the median
age at diagnosis for both mutation carriers and non-carriers
was 64 yr, p = 0.53. However, mutation carrier status was
significantly associated with more advanced PCa at time of
diagnosis. Mutation carriers had a higher proportion of
Gleason Score 7 (71%) than noncarriers (31%), p = 0.00009,
and higher median PSA levels (7.90 ng/ml) than noncarriers
(6.20 ng/ml), p = 0.048.
Mutation carrier status was significantly associated with
progression of PCa. Among lethal PCa patients, the mutation
carrier rates differed significantly 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 >75 yr,
respectively, p = 0.046 ). No mutations were
observed in 49 men dying from PCa over the age of 80 yr.
The mutation carrier rates also differed significantly as a
function of 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; .
The survival analysis in the entire cohort revealed that[14_TD$DIFF]
men with pathogenic/likely pathogenic mutation of these
three genes had a significantly shorter survival time ).
Themedian survival time after diagnosis was 5.0 yr in carriers
and 16.0 yr in noncarriers (Log-rank p = 3.7 10–10
[13_TD$DIFF]). The
association remained significant after adjusting for race and
age, PSA, and Gleason Score (< 7 vs 7) at the time of
diagnosis using the Cox regression analysis (hazard ra-
tio = 2.13, 95% confidence interval: 1.24–3.66, p = 0.006).
Additional analyses were performed in subgroups of
patients based on the disease status at time of diagnosis
(Figs. 2B and 2C, Supplementary Table 2). Mutation carrier
rate was highest in 122 lethal patients with the metastatic
disease at time of diagnosis (8.2%), followed by 94 lethal PCa
patients with localized disease at time of diagnosis (5.3%),
and 486 PCa patients diagnosed with low-risk localized
disease and remain localized at the time of the study (1.4%),
p = 5.4 10–5. Mutation carrier status was a significant
predictor of PCa-specific survival in patients diagnosed with
the metastatic disease at time of diagnosis (p = 3.8 10–4),
or in patients diagnosed with the localized disease at time of
diagnosis (p = 0.0013).
Similar results were found when analyses were per-
formed within each racial group ), although
most statistical significances were reached only in Europe-
an Americans, the largest racial group examined in this
study.
4. Discussion
In addition to confirming the major findings from previous
studies on association of germline mutations of BRCA2 and
risk/progression of PCa, results from this study [15_TD$DIFF]provide
novel findings that further substantiate roles of germline
mutations in these three DNA repair genes (BRCA2, ATM, and
BRCA1) in distinguishing lethal from indolent PCa and
predicting age of PCa-specific death. Our study is novel in
several respects. Firstly, it is the first report analyzing
germline mutations in these three genes in a large cohort of
men who died of PCa, an important but understudied group
of patients in previous studies . Furthermore,
few prior studies specifically included African American and
Asians patients. While larger studies are obviously needed,
the inclusion of men of African and Chinese descent in this
study provides some initial indications of the importance of
these genes in various populations.
Secondly, rather than relying on data from public
databases, we performed sequencing, variant calling, and
annotation in both groups of lethal and localized PCa patients
thereby facilitating an accurate comparison. This strategy
reduced the likelihood that some of differences between the
two groups of patients are results of technical aspects of
sequencing methods (coverage and depth). Comparing
mutation frequencies between lethal and localized PCa
patients within each racial group reduced the likelihood
that the observed difference is influenced by population
stratification (ie, difference in mutation frequencies being
Table 3 – Carrier rates of pathogenic/likely pathogenic mutations in BRCA1/2 and ATM by age of onset and age of death
N (%) of pathogenic/likely pathogenic mutations
All European American African American Chinese
All 19 (6.07) 14 (5.36) 1 (3.33) 4/22 (18.18)
Age of death (yr)
60 4/40 (10.00) 4/33 (12.12) 0/5 (0) 0/2 (0)
60–65 5/55 (9.09) 4/48 (8.33) 0/3 (0) 1/4 (25.00)
65–70 3/36 (8.33) 2/29 (6.90) 0/3 (0) 1/4 (25.00)
70–75 4/81 (4.94) 2/58 (3.45) 0/11 (0) 2/12 (16.67)
>75 3/101 (2.97) 2/93 (2.15) 1/8 (12.50) 0/0 (—)
p value 0.046 0.014 — —
Time to death, yr (from diagnosis)
5 13/106 (12.26) 8/73 (10.96) 1/11 (9.09) 4/22 (18.18)
5–10 5/105(4.76) 5/92 (5.43) 0/13 (0.00) 0/0 (0.00)
>10 1/102 (0.98) 1/96 (1.04) 0/6 (0.00) 0/0 (0.00)
p value 0.0006 0.004 0.25 —
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