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Our data are comparable with that of recent findings of
Pritchard et al
[25]who observed a mutation frequency of
7.80% in these three genes in men with metastatic PCa. An
inspection of the mutations found in the Pritchard et al
study
[25]reveals a significant fraction of founder muta-
tions in both
BRCA1
and
BRCA2
, mainly from a single study
site that is likely enriched for Ashkenazim, which may
explain the slightly higher mutation frequency observed in
their study
[31,32]. In our study there were three founder
mutation carriers, one in a lethal PCa patient and two in
localized PCa patients.
We followed the general guideline of American College of
Medical Genetics and Genomics to classify pathogenic and
likely pathogenic mutations in all patients, regardless of
disease status, as described in the Patients and methods
section.
[19_TD$DIFF]
Several of these mutations maybe debatable,
including two
BRCA2
truncating mutations (NM_000059.3:
c.10094_10095insGAATTATATC; p.S3366Nfs*5 in Patient
9 and NM_000059.3: c.10094_10095insGAATTATAT;
p.V3365_S3366insNYI in Patient 17; Supplementary
Table 1). Both mutations are in the
[20_TD$DIFF]
last exon of the
BRCA2
transcript. The first mutation cosegregates with lethal PCa
phenotype in this family (data not shown). If we remove
these two mutation carriers, the main results of our study
still hold; the frequency of pathogenic mutations was
significantly higher in lethal cases (17/313, 5.43%) than
localized cases (7/486, 1.44%),
p
= 0.001, and mutation
carriers remained an independent predictor of lethal PCa
after adjusting for race and age, PSA, and Gleason Score at the
time of diagnosis,
p
= 0.01. Another debatable mutation is
ATM
p.L950R (NM_000051.3: c.2849T
>
G). We
[21_TD$DIFF]
called this
mutation as likely pathogenic using our working criteria. In
addition, this mutation
[22_TD$DIFF]
is
[23_TD$DIFF]
called likely pathogenic in ClinVar
in Ataxia
[24_TD$DIFF]
-telangiectasia families and Leu950 is located in an
11-amino acid sequence 942
[25_TD$DIFF]
LHLHMYLM
L
.LK952 that is
conserved from human, cow, mouse, rat, to frog. Since this
mutation was found in a localized prostate cancer patient,
reclassifying this mutation to uncertain would not alter
[26_TD$DIFF]
but
rather slightly strengthen, our major results.
Limitations of our study include the small numbers of
mutation carriers, even though a relatively large number of
men who died fromPCa were studied, reflecting the rarity of
these mutations even in this enriched population. Indeed,
despite finding an elevated rate of mutations in men with
lethal PCa, the frequency of individual mutations is still
quite low, necessitating large sample numbers to establish
statistically significant, clinically meaningful associations
and provide reliable estimates of mutation
[27_TD$DIFF]
carrier rate.
Genetic analyses limited to point mutations and small
INDELs in this study, due to low confidence in detecting
large-size of DNA deletions and gains using next-generation
sequencing method, is another important limitation. We
did not adjust our results for effects of differing treatments
among the different sets of patients and how these
treatments may affect outcome, although given the strong
potential for a patient’s mutational status to influence
treatment, this question deserves much further study.
Focusing on only the three most established DNA repair
genes in this study is both limitation and strength. Many
other DNA repair genes such as
CHEK2
have been implicated
in some studies
[25]; however, evidence for their associa-
tions with risk and progression of PCa is still insufficient at
this point for the primary purpose of this study which
focuses on translation of more established germline
findings. Additional research studies of other DNA repair
genes and risk/progression of PCa in larger study popula-
tions are needed and undoubtedly underway. Finally, the
full impact of these
[28_TD$DIFF]
heterozygous germline mutations
cannot be fully appreciated without knowing the
[29_TD$DIFF]
somatic
status of the other allele
[4_TD$DIFF]
, as well as expression levels
reflecting possible epigenetic silencing of nonmutated
alleles.
5.
Conclusions
In summary, our study provides additional evidence that
the mutation status of
ATM
and
BRCA1/2
distinguishes the
risk for lethal and indolent PCa and is associated with earlier
age at death and shorter survival time. Together with
previous studies, the consistent findings to date may have
important clinical implications in genetic testing and
decision making for PCa screening and treatment.
Author contributions:
Jianfeng Xu had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design:
Xu, Isaacs, Ding.
Acquisition of data:
Zheng, Han, Ding, Ewing, Zhang, Novakovic, Quinn,
Wu, Khandekar, Petkewicz, Humphries, Wiley, Isaacs, Shen.
Analysis and interpretation of data:
Na, Yu, Jiang, Gulukota, Helseth Jr,
Hulick, Shevrin, Cooney, Partin, Carter, Carducci, Eisenberger, Den-
meade, McGuire, Walsh, Helfand, Brendler, Ding.
Drafting of the manuscript:
Na, Zheng, Han, Xu, Isaacs.
Critical revision of the manuscript for important intellectual content:
Hulick,
Shevrin, Cooney, Partin, Carter, Carducci, Eisenberger, Denmeade,
McGuire, Walsh, Helfand, Brendler, Ding.
Statistical analysis:
Na, Wang.
Obtaining funding:
Xu.
Administrative, technical, or material support:
Zheng, Shah, Liu, Zhang.
Supervision:
Isaacs, Xu, Ding.
Other:
None.
Financial disclosures:
Jianfeng Xu certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.
Funding/Support and role of the sponsor:
The study is partially supported
by the National Key Basic Research Program Grant 973 of China
(2012CB518301), the Key Project of the National Natural Science
Foundation of China (81130047), and the Rob Brooks Fund for Personalized
Cancer Care at NorthShore University HealthSystem
[30_TD$DIFF]
. Additional support
was provided by the Commonwealth Foundation, SKCCC (to WBI).
Acknowledgments:
The study is partially supported by the National Key
Basic Research Program Grant 973 of China (2012CB518301), the Key
Project of the National Natural Science Foundation of China (81130047),
and the Rob Brooks Fund for Personalized Cancer Care at NorthShore
University HealthSystem. We are also most grateful to the Ellrodt-
Schweighauser family for establishing an Endowed Chair of Cancer
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