JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T
Prediction of Breast and Prostate Cancer Risks inMale BRCA1
and BRCA2 Mutation Carriers Using Polygenic Risk Scores
Julie Lecarpentier, Valentina Silvestri, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Penny
Soucy, Goska Leslie, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, Andrew Lee, Ali Amin Al Olama,
Jonathan P. Tyrer, Melissa Southey, Esther M. John, Thomas A. Conner, David E. Goldgar, Saundra S. Buys, Ramunas
Janavicius, Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, Thomas V.O. Hansen, Ana Osorio, Jeffrey N. Weitzel,
Angela Toss, Veronica Medici, Laura Cortesi, Ines Zanna, Domenico Palli, Paolo Radice, Siranoush Manoukian, Bernard
Peissel, Jacopo Azzollini, Alessandra Viel, Giulia Cini, Giuseppe Damante, Stefania Tommasi, Paolo Peterlongo, Florentia
Fostira, Ute Hamann, D. Gareth Evans, Alex Henderson, Carole Brewer, Diana Eccles, Jackie Cook, Kai-ren Ong, Lisa
Walker, Lucy E. Side, Mary E. Porteous, Rosemarie Davidson, Shirley Hodgson, Debra Frost, Julian Adlard, Louise Izatt, Ros
Eeles, Steve Ellis, Marc Tischkowitz, EMBRACE, Andrew K. Godwin, Alfons Meindl, Andrea Gehrig, Bernd Dworniczak,
Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Eric Hahnen, Jan Hauke, Kerstin Rhiem, Karin
Kast, Norbert Arnold, Nina Ditsch, ShanWang-Gohrke, Barbara Wappenschmidt, Dorothea Wand, Christine Lasset,
Dominique Stoppa-Lyonnet, Muriel Belotti, Francesca Damiola, Laure Barjhoux, Sylvie Mazoyer, GEMO Study
Collaborators, Mattias Van Heetvelde, Bruce Poppe, Kim De Leeneer, Kathleen B.M. Claes, Miguel de la Hoya, Vanesa
Garcia-Barberan, Trinidad Caldes, Pedro Perez Segura, Johanna I. Kiiski, Kristiina Aittoma¨ki, Sofia Khan, Heli Nevanlinna,
Christi J. van Asperen, HEBON, Tibor Vaszko,Miklos Kasler, EdithOlah, Judith Balmaña, SaraGutie´rrez-Enr´ıquez, Orland
Diez, AlexTeul´e, Angel Izquierdo, EstherDarder, JoanBrunet, Jesu´sDelValle, Lidia Feliubadalo,Miquel Angel Pujana,Conxi
Lazaro, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th. Johannsson, Rosa B. Barkardottir, Elisa Alducci, Silvia Tognazzo,
MarcoMontagna,Manuel R. Teixeira, Pedro Pinto, Amanda B. Spurdle, Helene Holland, KConFab Investigators, JongWon
Lee, Min Hyuk Lee, Jihyoun Lee, Sung-Won Kim, Eunyoung Kang, Zisun Kim, Priyanka Sharma, Timothy R. Rebbeck,
Joseph Vijai, Mark Robson, Anne Lincoln, JacobMusinsky, PragnaGaddam, Yen Y. Tan, Andreas Berger, Christian F. Singer,
Jennifer T. Loud, Mark H. Greene, AnnaMarie Mulligan, Gord Glendon, Irene L. Andrulis, Amanda Ewart Toland, Leigha
Senter, Anders Bojesen, Henriette Roed Nielsen, Anne-Bine Skytte, Lone Sunde, Uffe Birk Jensen, Inge Sokilde Pedersen, Lotte
Krogh, Torben A. Kruse, Maria A. Caligo, Sook-Yee Yoon, Soo-Hwang Teo, Anna vonWachenfeldt, Dezheng Huo, SarahM.
Nielsen, Olufunmilayo I. Olopade, Katherine L. Nathanson, Susan M. Domchek, Christa Lorenchick, Rachel C. Jankowitz,
Ian Campbell, Paul James, Gillian Mitchell, Nick Orr, Sue Kyung Park, Mads Thomassen, Kenneth Offit, Fergus J. Couch,
Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Rita K. Schmutzler, Antonis C. Antoniou, and Laura Ottini
A B S T R A C T
Purpose
BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants
modify cancer risks for female carriers of BRCA1/2mutations.We investigated—for the first time to our
knowledge—associations of common genetic variants with breast and prostate cancer risks for male
carriers of BRCA1/2 mutations and implications for cancer risk prediction.
Materials and Methods
Wegenotyped1,802male carriers ofBRCA1/2mutations from theConsortiumof InvestigatorsofModifiers
ofBRCA1/2 by using the custom IlluminaOncoArray.We investigated the combined effects of established
breast and prostate cancer susceptibility variants on cancer risks formale carriers ofBRCA1/2mutations by
constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.
Results
In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility
variantswas associatedwith breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95%CI, 1.19
to 1.56; P = 8.63 1026). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was
associatedwith prostate cancer risk (odds ratio per SD of PRS, 1.56; 95%CI, 1.35 to 1.81;P= 3.23 1029).
Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For
example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from7% to
26% for carriers ofBRCA1mutations and from19% to 61% for carriers ofBRCA2mutations, respectively.
Conclusion
PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2mutations that
might enable these men and their physicians to make informed decisions on the type and timing of
breast and prostate cancer risk management.
J Clin Oncol 35:2240-2250. © 2017 by American Society of Clinical Oncology. Licensed under the
Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/
Author affiliations and support information
(if applicable) appear at the end of this
article.
Published at jco.org on April 27, 2017.
J.L. and V.S. contributed equally to this
work as co-first authors.
R.K.S., A.C.A., and L.O. contributed
equally to this work as co-last authors.
The content of this manuscript does not
necessarily reflect the views or policies of
the National Cancer Institute or any of the
collaborating centers in the Breast Cancer
Family Registry (BCFR), nor does mention
of trade names, commercial products, or
organizations imply endorsement by the US
Government or the BCFR. The content is
solely the responsibility of the authors and
does not necessarily represent the official
views of the National Institutes of Health.
Corresponding author: Laura Ottini, MD,
Department of Molecular Medicine,
Sapienza University of Rome, Viale Regina
Elena, 324, 00161, Rome, Italy; e-mail:
laura.ottini@uniroma1.it.
© 2017 by American Society of Clinical
Oncology. Licensed under the Creative
Commons Attribution 4.0 License.
0732-183X/17/3520w-2240w/$20.00
ASSOCIATED CONTENT
See accompanying Editorial
on page 2224
Data Supplement
DOI: https://doi.org/10.1200/JCO.
2016.69.4935
DOI: https://doi.org/10.1200/JCO.2016.
69.4935
2240 © 2017 by American Society of Clinical Oncology
VOLUME 35 • NUMBER 20 • JULY 10, 2017
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
INTRODUCTION
Germline mutations in BRCA1 and, predominantly, BRCA2 are
associated with increased risks in men of developing breast and
prostate cancers.1,2 BRCA1/2mutations account for approximately
10% of male breast cancer and 2% of prostate cancer cases.3-5
Breast cancer in men is rare and accounts for less than 1% of all
male tumors. By contrast, prostate cancer is the most common
cancer in men, accounting for approximately 25% of male tu-
mors.6 The lifetime risk of male breast cancer in mutation carriers
has been estimated to be 5% to 10% and 1% to 5% for carriers of
BRCA2 and BRCA1 mutations, respectively, whereas estimates of
lifetime prostate cancer risk are approximately 20% and 40% for
carriers of BRCA1 and BRCA2 mutations, respectively.3,7-10
More than 100 common genetic variants (single nucleotide
polymorphisms [SNPs]) that are associated with prostate cancer
and female breast cancer have been identified via genome-wide
association studies (GWAS) in the general population,11,12 and
their combined effects have been shown to have significant im-
plications for risk stratification and targeted prevention.13-15 By
contrast, only two male breast cancer susceptibility SNPs have been
identified to date,16 but there is some evidence that suggests that
common variants that are associated with female breast cancer may
influence male breast cancer risk.17-19
Studies by the Consortium of Investigators of Modifiers of
BRCA1/2 (CIMBA) have shown that common SNPs modify the
risk of breast and ovarian cancers for female BRCA1 and BRCA2
mutation carriers20-22; however, no study to date has investigated
the associations of common SNPs with breast or prostate cancer
risk for men with BRCA1/2 mutations and their implications for
cancer risk prediction.
In this study, we performed the first GWAS for breast and
prostate cancers in male BRCA1/2 mutation carriers enrolled in
CIMBA using the custom Illumina OncoArray. Furthermore, we
evaluated the combined effects of known common breast and
prostate cancer susceptibility variants on cancer risks for male
carriers of BRCA1/2mutations and estimated absolute age-specific
cumulative risks of developing breast and prostate cancers on the
basis of combined SNP distributions. We demonstrate—to our
knowledge for the first time—that combined SNP effects have
important implications for risk profiling of male carriers of
BRCA1/2 mutations.
MATERIALS AND METHODS
Samples
CIMBA collects data on men with BRCA1 or BRCA2 clearly path-
ogenic variants—commonly termedmutations—who are older than 18 years,
with the majority recruited via cancer genetics clinics.23 Pathogenic variants
were defined as previously described.24 All participating studies have been
approved by local ethical review committees.
To select samples for genotyping, we used a case-control study design,
selecting all available male carriers of BRCA1/2 mutations who were af-
fected with breast and/or prostate cancer (cases) and matching them with
up to three unaffected mutation carriers (controls). Cases and controls
were matched for study group or country of residence, year of birth, and
gene (BRCA1 or BRCA2). A total of 1,989 male carriers were selected for
genotyping: 265 with breast cancer, 212 with prostate cancer, 43 with both
diseases, and 1,469 unaffected.
Genotyping and Quality Control
Genotyping was performed by using the Illumina OncoArray
beadchip (approximately 570,000 SNPs with genome-wide coverage).
Genotyping and quality control were performed as described in the Data
Supplement. Of 1,989 samples, 1,802 passed the quality control step. We
imputed genotypes using the 1000 Genomes Project as the reference panel
(Data Supplement).
Statistical Methods
Association Analyses. We evaluated associations of SNPs with risks
of breast and prostate cancer simultaneously using multinomial logistic
regression. The control group in this analysis was defined as the set of
samples without a breast or prostate cancer diagnosis. Breast and prostate
cancer cases were defined on the basis of age at diagnosis, whichever
occurred first. If breast and prostate cancer occurred at the same time,
individuals were treated as patients with breast cancer. Thus, of 1,802
samples, 277 were defined as patients with breast cancer, 212 as patients
with prostate cancer, and 1,313 as controls. Analyses were adjusted for
the first three principal components, age at breast or prostate cancer for
patient-cases and age at interview for controls, and gene (BRCA1 or
BRCA2). A robust variance approach—clustering of family member-
ship—was used to adjust for related individuals. Additional logistic
regression analyses were carried out to assess associations separately with
breast or prostate cancer risk (Data Supplement). We also performed
a set of sensitivity analyses by considering patient cases with both breast
and prostate cancer as a separate group in a multinomial logistic
regression model (Data Supplement). Analysis was performed in R
(version 3.2.3; R Foundation, Vienna, Austria) and STATA software
(version 13.1; STATA, College Station, TX; Computing Resource
Center, Santa Monica, CA).
Polygenic Risk Scores. Assuming a log-additive model for the joint
effects of SNPs, we constructed polygenic risk scores (PRSs) by summing
the number of alleles across SNPs that were weighted by their estimated
per-allele log-odds ratios (ORs) in published studies11,12,22,25-32 (Data
Supplement).
PRSs were standardized to have mean 0 and variance 1 (Data
Supplement). We evaluated associations with quartiles of PRS on the basis
of the PRS distribution in controls. Absolute age-specific cumulative risks
of developing breast or prostate cancer at different percentiles of PRS were
calculated using published methods33 (Data Supplement).
Selection of SNPs Included in PRSs and Weights. Breast Cancer
PRSs. We investigated three main PRSs using SNPs that were known to be
associated with overall risk of breast cancer or risk of estrogen receptor
(ER)–positive or –negative breast cancer from published studies that were
performed in females from the general population. To construct each PRS
and to avoid over-fitting, we used external log-OR estimates—for their
association with risk for overall breast cancer or ER-positive or ER-negative
breast cancer—from the largest association studies of the Breast Cancer
Association Consortium.12,22,28-31,34 No data from the current study were
used to construct any of the PRSs. The three PRSs were defined as follows:
1. The overall PRS includes SNPs that were associated with breast cancer
risk from population-based association studies. This PRS included 88
(77 genotyped, 11 imputed) SNPs.
2. The ER-positive PRS includes SNPs that were associated with ER-
positive breast cancer. This PRS included 87 (76 genotyped, 11
imputed) SNPs. Weights for each SNP were based on published log-
OR estimates for ER-positive breast cancer.
3. The ER-negative PRS includes SNPs associated with ER-negative
disease. This PRS included 53 (47 genotyped, six imputed) SNPs.
Weights for each SNP were based on log-OR estimates for ER-
negative breast cancer.
jco.org © 2017 by American Society of Clinical Oncology 2241
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
A list of SNPs and weights used in each PRS is shown in the Data
Supplement. To identify the most strongly associated PRS, we have
evaluated the associations of all three PRSs in the set of BRCA1 and BRCA2
samples combined and separately.
We also investigated two PRSs by using SNPs that were associated
with breast cancer risk for female BRCA1/2 mutation carriers (Data
Supplement).
Prostate Cancer PRS. Prostate cancer PRS included variants that
were associated with prostate cancer at genome-wide significant level in
studies of the PRACTICAL consortium.11,14,32,35-38 Log-OR estimates from
published population-based studies were used according to the approach
above.11,32 This PRS included 103 (71 genotyped, 32 imputed) SNPs (Data
Supplement).
RESULTS
We evaluated associations for a total of 9,530,887 SNPs in 1,802
male carriers of BRCA1/2 mutations, including 277 patients with
breast cancer, 212 patients with prostate cancer, and 1,313
controls. We investigated associations in the combined sample of
BRCA1/2 mutation carriers and separately in BRCA2 mutation
carriers. The number of BRCA1 mutation carriers was too small
to allow for separate analyses. Across the two analyses, no as-
sociations at P , 1028 were identified. A total of 577 SNPs
exhibited associations at P , 1025. GWAS results are reported in
the Data Supplement.
Breast Cancer PRSs
Of 102 SNPs included in the breast cancer PRSs, 68 SNPs
(67%) yielded OR estimates in the same direction as those that
have been previously reported for females in the general pop-
ulation. Eleven SNPs were associated with breast cancer risk at
P , .05 (Data Supplement). After accounting for multiple testing,
there was no evidence of pairwise interactions between any two
variants in the PRSs.
The three main breast cancer PRSs that were constructed on
the basis of associations with female breast cancer risk were
strongly associated with male breast cancer risk for both BRCA1
and BRCA2mutation carriers (Table 1). The OR estimate for male
breast cancer per standard deviation (SD) increase in overall PRS
was estimated to be 1.36 (95% CI, 1.19 to 1.56; P = 8.63 1026) in
combined BRCA1/2 carriers. Associations remained significant
when BRCA1 and BRCA2 carriers were analyzed separately
(BRCA1: OR, 1.49; 95% CI, 1.07 to 2.07; P = .019; BRCA2: OR,
1.36; 95% CI, 1.17 to 1.58; P = 7.23 1025). Men in the 3rd and 4th
quartiles were at significantly increased risk of breast cancer
compared with men in the bottom quartile of the PRS (Table 1),
but the numbers of carriers in individual quartiles in the BRCA1
only analyses were too small to draw definitive conclusions.
The magnitude and strength of associations were similar for
the PRS that was constructed on the basis of SNPs associated with
ER-positive breast cancer in females (Table 1). The ER-negative
PRS showed a weaker association with breast cancer risk for male
carriers of BRCA1/2 mutations. Results were similar when the
associations were evaluated using logistic regression (Data Sup-
plement) and when considering the patients with both breast and
prostate cancer as a separate group in a multinomial logistic re-
gression model (Data Supplement).
Prostate Cancer PRS
Of 103 SNPs that were included in the prostate cancer PRS, 74
SNPs (71%) had estimated ORs in the same direction as those
previously reported in population-based studies. Eight SNPs were
associated at P , .05 (Data Supplement).
There was a highly significant association between the prostate
cancer PRS and prostate cancer risk for male carriers of BRCA1/2
mutations (OR for prostate cancer per SD increase, 1.56; 95% CI,
1.35 to 1.81; P = 3.2 3 1029; Table 2). Associations remained
significant when analyses were performed separately for carriers of
BRCA1 and BRCA2mutations (BRCA1: OR, 1.72; 95% CI, 1.30 to
2.29; P = 1.8 3 1024; BRCA2: OR, 1.49; 95% CI, 1.26 to 1.77;
P = 4.9 3 1026). There was an increasing risk of prostate cancer
with increasing PRS quartiles. When compared with the 1st
quartile, OR for prostate cancer for men in the 2nd quartile was
1.82 (95% CI, 1.07 to 3.08; P = .026), for men in the 3rd quartile,
2.23 (95% CI, 1.32 to 3.76; P = .003), and for men in the 4th
quartile, 3.36 (95% CI, 2.05 to 5.52; P = 1.7 3 1026).
We observed significant associations between prostate cancer
PRS with both low (, 7) and high ($ 7) Gleason score prostate
cancers (Table 2). There was no evidence of interaction between
age at diagnosis and/or observation and any breast or prostate
cancer PRSs (Data Supplement).
Discriminatory Ability
The overall breast cancer and ER-positive PRSs had an area
under the curve (AUC) of 0.59 (95% CI, 0.55 to 0.63). ER-negative
PRS had the lowest AUC at 0.55 (95% CI, 0.51 to 0.59). The AUC
for prostate cancer PRS was estimated to be 0.62 (95% CI, 0.58 to
0.66).
Predicted Risks of Male Breast and Prostate Cancer by
PRS Percentile
We used the estimated OR for the breast cancer overall PRS
and the prostate cancer PRS from the combined analysis of
BRCA1/2 samples to calculate male breast and prostate cancer risks
at the 5th, 10th, 50th, 90th, and 95th percentiles of PRS distri-
butions (Figs 1, 2, and 3 and Data Supplement). There were large
differences in absolute risks between percentile groups. For BRCA2
carriers, the risk of breast cancer by age 80 years is 5% for men at
the 5th percentile of the PRS and 14% for men at the 95th per-
centile; the risk of prostate cancer by age 80 years is 19% for men at
the 5th percentile of the PRS and 61% for men at the 95th per-
centile. For carriers of BRCA1mutations, men at the 5th percentile
of the prostate cancer PRS have a 7% risk of developing prostate
cancer by age 80, and men at the 95th percentile of the PRS
distribution have a prostate cancer risk of 26%.
DISCUSSION
We performed the first GWAS, to our knowledge, in male carriers
of BRCA1/2 mutations to identify common variants that modify
the risks of breast and prostate cancer in these men. Although we
analyzed the largest series of male mutation carriers available, this
study is underpowered to detect associations with individual low-
risk SNPs.
2242 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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jco.org © 2017 by American Society of Clinical Oncology 2243
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
Downloaded from ascopubs.org by CNIO-FUND on September 27, 2019 from 193.147.150.201
Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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2244 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
We have demonstrated that the combined effects of known
breast cancer susceptibility SNPsmodify breast cancer risk for male
mutation carriers and, separately, that the combined effects of
known prostate cancer susceptibility SNPs modify prostate cancer
risk for male mutation carriers.
PRSs that were constructed with SNPs for female breast cancer
and prostate cancer in the general population are highly predictive
of risk in male carriers of BRCA1/2 mutations. These results
provide the first direct evidence of overlap in the genetic sus-
ceptibility to female breast and prostate cancers in the general
population as well as the modification of risks of male breast and
prostate cancer in men with BRCA1/2 mutations.
We estimated anOR for breast cancer of 1.36 per SD increase in
the overall breast cancer PRS. No study in the general population has
assessed this exact PRS yet, but Mavaddat et al15 estimated an OR for
female breast cancer of 1.55 for a PRS based on a subset of SNPs in
females. Although the present estimate in males is not significantly
different from that observed in females, it is somewhat lower. A
lower OR may be a result of certain breast cancer SNPs that were
included in the PRS that are not associated with male breast cancer
risk, or individual SNPsmay have smaller ORs formale breast cancer
than female breast cancer. Alternatively, the estimate of Mavaddat
et al15 may be susceptible to some level of winner’s curse bias.
The prostate cancer PRS was associated with prostate cancer
risk in male carriers of BRCA1/2mutations, with an OR of 1.56 per
SD increase in PRS. A previous study on prostate cancer PRS in the
general population estimated an OR of 1.74.14
Overall, our results indicate that population-based breast and
prostate cancer PRSs are predictive of cancer risk for male
mutation carriers, which suggests a general model of susceptibility
under which BRCA1/2 mutations and other common cancer
susceptibility variants interact multiplicatively on the risk of de-
veloping breast and prostate cancers.
To calculate PRSs we have used SNPs and corresponding log-
OR estimates from external, population-based studies; therefore,
the present analysis represents an independent validation of those
externally derived PRSs and indicates that they are independently
predictive of cancer risks for male carriers of BRCA1/2 mutations.
Although the present analysis was based on a case-control study
design, information on SNPs is not subject to the usual biases that
are associated with retrospective studies (eg, recall biases);
therefore, the reported associations between the PRSs investigated
and cancer risks are unlikely to be influenced by the study design.
The ER-positive PRS had a stronger association with male
breast cancer in BRCA1/2 mutation carriers than did the
ER-negative PRS, which was in line with the observation that the
majority of male patients with breast cancer among BRCA1/2
mutation carriers are ER positive.23
We observed large differences in absolute risk between men in
the bottom and the top of the PRS distribution. In particular, prostate
cancer risk by age 80 years for male carriers of BRCA1 mutations
ranges from 7% for those at the bottom 5% of the risk distribution to
26% for those at the top 5% of the PRS distribution. By age 80 years,
male carriers of BRCA2 mutations are predicted to have a risk of
prostate cancer that ranges from 19% for those at the bottom 5% of
the risk distribution to 61% for those at the top 5% of the distri-
bution, and a breast cancer risk that ranges from 5% to 14%.
In these calculations, we assumed conservative average
prostate cancer risks for both BRCA1 and BRCA2 mutations;
however, higher estimates for the effect of BRCA1/2 mutations
have been reported in the literature.4,9 Prospective studies of male
mutation carriers will be useful for assessing the calibration of
absolute cancer risks by PRS percentiles; however, such studies are
not currently available with sufficiently large numbers of incident
male breast and prostate cancer cases.
Although there are no established screening or intervention
strategies for male carriers of BRCA1/2 mutations, few clinical
management recommendations include education, clinical breast
examination, and prostate cancer screening.39 The present findings
may inform the development of clinical recommendations on the
basis of polygenic risk stratification of male mutation carriers to
personalize management recommendations. For example, the current
40 50 60 70 80
Age (years)
10th and 90th percentiles
5th and 95th percentiles
Median
0
10
20
30
40
50
60
70
80
Cu
m
ul
at
iv
e 
Ri
sk
 (%
)
Fig 3. Predicted prostate cancer cumulative risk for male carriers of BRCA2
mutations by percentiles of prostate cancer polygenic risk score that was con-
structed by using results from population-based studies.
0
5
10
15
20
40 50 60 70 80
Cu
m
ul
at
iv
e 
Ri
sk
 (%
)
Age (years)
10th and 90th percentiles
5th and 95th percentiles
Median
Fig 1. Predicted breast cancer cumulative risk for male carriers of BRCA2
mutations by percentile of overall polygenic risk score that was constructed by
using results from population-based studies.
Cu
m
ul
at
iv
e 
Ri
sk
 (%
)
40 50 60 70 80
Age (years)
10th and 90th percentiles
5th and 95th percentiles
Median
0
5
10
15
20
25
30
35
40
Fig 2. Predicted prostate cancer cumulative risk for male carriers of BRCA1
mutations by percentiles of prostate cancer polygenic risk score that was con-
structed by using results from population-based studies.
jco.org © 2017 by American Society of Clinical Oncology 2245
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
Downloaded from ascopubs.org by CNIO-FUND on September 27, 2019 from 193.147.150.201
Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
United KingdomNICE guidelines recommend enhanced surveillance
for women with a lifetime risk greater than 17% of developing breast
cancer, regardless of their BRCA1/2 status.40 Similar approaches may
be developed for male carriers of BRCA1/2 mutations for whom
management would differ on the basis of their individual lifetime risk.
For example, on the basis of the prostate cancer PRS, 43%ofmenwith
BRCA1 mutations are predicted to have a prostate cancer risk of
greater than 17% and may benefit from enhanced screening, whereas
those at lower risk may opt for more limited surveillance.
Our data provide a strong impetus for new prospective screening
studies in high-risk cohorts, such as the IMPACT trial,41 to include
genetic risk assessment by PRSs in study protocols to assess the impact
of cancer risk stratification in male mutation carriers. Recently, it has
been suggested that polygenic risk-stratified screening can reduce
overdiagnosis in the general population.42-44 Similar arguments may
apply to male mutation carriers in whom polygenic risk prediction
may further improve the effectiveness of screening.
A potential limitation of the current study is that family
history information was not readily available for mutation carriers;
therefore it was not possible to assess how the prostate and breast
cancer risks in male carriers that are associated with PRSs vary by
family history. Although this would not invalidate the association
results, considering the effect of family history will be important in
the context of genetic counseling.
Men with BRCA1/2 mutations represent a small but unique
patient group in terms of clinical management. Our results suggest
that risk profiling on the basis of PRSs may identify male carriers of
BRCA1/2 mutations at both sufficiently reduced or increased risk of
breast or prostate cancer, with implications for their clinical man-
agement. To facilitate this, it will be important to incorporate such
PRSs into breast or prostate cancer risk prediction algorithms.45
As an accurate risk assessment is the basis of cancer prevention
and screening strategies, the PRSs presented here may be used to
provide male carriers of BRCA1/2 mutations and their physicians
with more detailed information on their breast and prostate cancer
risks to aid prevention and screening decisions.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Georgia Chenevix-Trench, Rita K. Schmutzler,
Antonis C. Antoniou, Laura Ottini
Administrative support: Antonis C. Antoniou
Provision of study materials or patients: Melissa Southey, Ramunas
Janavicius, Yuan Chun Ding, Paolo Radice, Karin Kast, Kathleen B.M.
Claes, Heli Nevanlinna, Gord Glendon, Sook-Yee Yoon, Katherine L.
Nathanson, Antonis C. Antoniou
Collection and assembly of data: Valentina Silvestri, Daniel Barrowdale,
Joe Dennis, Lesley McGuffog, Penny Soucy, Goska Leslie, Piera Rizzolo,
Anna Sara Navazio, Virginia Valentini, Veronica Zelli, Andrew Lee, Ali
Amin Al Olama, Jonathan P. Tyrer, Melissa Southey, Esther M. John,
Thomas A. Conner, David E. Goldgar, Saundra S. Buys, Ramunas
Janavicius, Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, Thomas
V.O. Hansen, Ana Osorio, Jeffrey N.Weitzel, Angela Toss, VeronicaMedici,
Laura Cortesi, Ines Zanna, Domenico Palli, Paolo Radice, Siranoush
Manoukian, Bernard Peissel, Jacopo Azzollini, Alessandra Viel, Giulia Cini,
Giuseppe Damante, Stefania Tommasi, Paolo Peterlongo, Florentia Fostira,
Ute Hamann, D. Gareth Evans, Alex Henderson, Carole Brewer, Diana
Eccles, Jackie Cook, Kai-ren Ong, Lisa Walker, Lucy E. Side, Mary E.
Porteous, Rosemarie Davidson, Shirley Hodgson, Debra Frost, Julian
Adlard, Louise Izatt, Ros Eeles, Steve Ellis, Marc Tischkowitz, Andrew K.
Godwin, Alfons Meindl, Andrea Gehrig, Bernd Dworniczak, Christian
Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Eric
Hahnen, Jan Hauke, Kerstin Rhiem, Karin Kast, Norbert Arnold, Nina
Ditsch, Shan Wang-Gohrke, Barbara Wappenschmidt, Dorothea Wand,
Christine Lasset, Dominique Stoppa-Lyonnet, Muriel Belotti, Francesca
Damiola, Laure Barjhoux, Sylvie Mazoyer, Mattias Van Heetvelde, Bruce
Poppe, Kim De Leeneer, Kathleen B.M. Claes, Miguel de la Hoya, Vanesa
Garcia-Barberan, Trinidad Caldes, Pedro Perez Segura, Johanna I. Kiiski,
Kristiina Aittoma¨ki, Sofia Khan, Heli Nevanlinna, Christi J. van Asperen,
Tibor Vaszko, Miklos Kasler, Edith Olah, Judith Balmaña, Sara Gutie´rrez-
Enrı´quez, Orland Diez, Alex Teule´, Angel Izquierdo, Esther Darder, Joan
Brunet, Jesu´s Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, Conxi
Lazaro, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th. Johannsson, Rosa
B. Barkardottir, Elisa Alducci, Silvia Tognazzo, Marco Montagna, Manuel
R. Teixeira, Pedro Pinto, Amanda B. Spurdle, Helene Holland, Jong Won
Lee, Min Hyuk Lee, Jihyoun Lee, Sung-Won Kim, Eunyoung Kang, Zisun
Kim, Priyanka Sharma, Timothy R. Rebbeck, Joseph Vijai, Mark
Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, Yen Y. Tan,
Andreas Berger, Christian F. Singer, Jennifer T. Loud, Mark H. Greene,
Anna Marie Mulligan, Gord Glendon, Irene L. Andrulis, Amanda Ewart
Toland, Leigha Senter, Anders Bojesen, Henriette Roed Nielsen,
Anne-Bine Skytte, Lone Sunde, Uffe Birk Jensen, Inge Sokilde
Pedersen, Lotte Krogh, Torben A. Kruse, Maria A. Caligo, Sook-Yee
Yoon, Soo-Hwang Teo, Anna von Wachenfeldt, Dezheng Huo, Sarah M.
Nielsen, Olufunmilayo I. Olopade, Katherine L. Nathanson, Susan M.
Domchek, Christa Lorenchick, Rachel C. Jankowitz, Ian Campbell,
Paul James, Gillian Mitchell, Nick Orr, Sue Kyung Park, Mads
Thomassen, Kenneth Offit, Fergus J. Couch, Jacques Simard, Douglas F.
Easton, Georgia Chenevix-Trench, Rita K. Schmutzler, Antonis C.
Antoniou, Laura Ottini
Data analysis and interpretation: Julie Lecarpentier, Valentina Silvestri,
Karoline B. Kuchenbaecker, Ali Amin Al Olama, Rita K. Schmutzler,
Antonis C. Antoniou, Laura Ottini
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
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Affiliations
Julie Lecarpentier, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Goska Leslie, Andrew Lee, Ali
Amin Al Olama, Jonathan P. Tyrer, Debra Frost, Steve Ellis, Douglas F. Easton, and Antonis C. Antoniou, University of Cambridge;
Karoline B. Kuchenbaecker, The Wellcome Trust Sanger Institute, Hinxton; Marc Tischkowitz, Addenbrooke’s Treatment Centre,
Addenbrooke’s Hospital, Cambridge;D. Gareth Evans, Manchester University, Central Manchester University Hospitals NHS Foundation
Trust, Manchester; Alex Henderson, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Carole Brewer, Royal Devon and
Exeter Hospital, Exeter; Diana Eccles, Southampton University Hospitals NHS Trust, Southampton; Jackie Cook, Sheffield Children’s
Hospital, Sheffield;Kai-ren Ong, BirminghamWomen’s Hospital Healthcare NHS Trust, Edgbaston, Birmingham; LisaWalker, Churchill
Hospital, Oxford; Lucy E. Side, Great Ormond Street Hospital for Children NHS Trust; Shirley Hodgson, St George’s, University of
London; Louise Izatt, Guy’s and St Thomas’NHS Foundation Trust; Ros Eeles, The Institute of Cancer Research and Royal Marsden NHS
Foundation Trust; Nick Orr, The Institute of Cancer Research, London; Mary E. Porteous, Western General Hospital, Edinburgh;
Rosemarie Davidson, South Glasgow University Hospitals, Glasgow; Julian Adlard, Chapel Allerton Hospital, Leeds, United Kingdom;
Valentina Silvestri, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, and Laura Ottini, Sapienza University of
Rome, Rome; Angela Toss, Veronica Medici, and Laura Cortesi, University of Modena and Reggio Emilia, Modena; Ines Zanna and
jco.org © 2017 by American Society of Clinical Oncology 2247
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
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Domenico Palli, Cancer Research and Prevention Institute, Florence; Paolo Radice, Siranoush Manoukian, Bernard Peissel, and Jacopo
Azzollini, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (INT); Paolo Peterlongo,
Italian Foundation for Cancer Research Institute of Molecular Oncology (IFOM), Milan; Alessandra Viel and Giulia Cini, CRO Aviano,
National Cancer Institute, Aviano; Giuseppe Damante, University of Udine, Udine; Stefania Tommasi, Istituto Nazionale Tumori
“Giovanni Paolo II”, Bari; Elisa Alducci, Silvia Tognazzo, andMarcoMontagna, Veneto Institute of Oncology IOV- IRCCS, Padua;Maria
A. Caligo, University and University Hospital of Pisa, Pisa, Italy; Penny Soucy and Jacques Simard, Centre Hospitalier Universitaire de
Que´bec Research Center and Laval University, Quebec City, Quebec; Anna Marie Mulligan and Irene L. Andrulis, University of Toronto;
Gord Glendon and Irene L. Andrulis, Mount Sinai Hospital, Toronto, Ontario, Canada;Melissa Southey, Ian Campbell, Paul James, and
Gillian Mitchell, University of Melbourne, Parkville, Victoria; Amanda B. Spurdle, Helene Holland, and Georgia Chenevix-Trench,
QIMR Berghofer Medical Research Institute, Brisbane, Queensland; Ian Campbell, Paul James, and Gillian Mitchell, Peter MacCallum
Cancer Centre, East Melbourne, New South Wales, Australia; Esther M. John, Cancer Prevention Institute of California, Fremont; Linda
Steele, Yuan Chun Ding, Susan L. Neuhausen, and Jeffrey N. Weitzel, City of Hope, Duarte, CA; Thomas A. Conner and Saundra S.
Buys, Huntsman Cancer Institute; David E. Goldgar, University of Utah School of Medicine, Salt Lake City, UT; Andrew K. Godwin,
University of Kansas Medical Center, Kansas City; Priyanka Sharma, University of Kansas Medical Center, Westwood, KS; Timothy R.
Rebbeck, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, MA; Joseph Vijai,Mark Robson, Anne
Lincoln, Jacob Musinsky, Pragna Gaddam, and Kenneth Offit, Memorial Sloan Kettering Cancer Center, New York, NY; Jennifer T.
Loud and Mark H. Greene, National Cancer Institute, Bethesda, MD; Amanda Ewart Toland and Leigha Senter, The Ohio State
University, Columbus, OH; Dezheng Huo, Sarah M. Nielsen, and Olufunmilayo I. Olopade, University of Chicago Medical Center,
Chicago, IL; Katherine L. Nathanson and Susan M. Domchek, University of Pennsylvania, Philadelphia; Christa Lorenchick and Rachel
C. Jankowitz, University of Pittsburgh Medical Center, Pittsburgh, PA; Fergus J. Couch, Mayo Clinic, Rochester, MN; Ramunas
Janavicius, State Research Institute Innovative Medicine Center, Vilnius, Lithuania; Thomas V.O. Hansen, Rigshospitalet, Copenhagen
University Hospital, Copenhagen; Anders Bojesen andHenriette Roed Nielsen, Vejle Hospital, Vejle;Anne-Bine Skytte, Lone Sunde, and
Uffe Birk Jensen, Aarhus University Hospital, Aarhus; Inge Sokilde Pedersen, Aalborg University Hospital, Aalborg; Lotte Krogh, Torben
A. Kruse, and Mads Thomassen, Odense University Hospital, Odense, Denmark; Ana Osorio, National Cancer Research Centre and
Spanish Network on Rare Diseases; Miguel de la Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, and Pedro Perez Segura, Hospital
Clinico San Carlos, El Instituto de Investigacio´n Sanitaria del Hospital Clı´nico San Carlos, Madrid; Judith Balmaña, University Hospital,
Vall d’Hebron; Sara Gutie´rrez-Enrı´quez and Orland Diez, Vall d’Hebron Institute of Oncology; Orland Diez, University Hospital Vall
d’Hebron; Alex Teule´, Jesu´s Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, and Conxi Lazaro, Bellvitge Biomedical Research
Institute, Catalan Institute of Oncology, Barcelona; Angel Izquierdo, Esther Darder, and Joan Brunet, Institut d’Investigacio´ Biome`dica
de Girona, Catalan Institute of Oncology, Girona, Spain; Florentia Fostira, National Centre for Scientific Research “Demokritos,” Athens,
Greece; Ute Hamann, German Cancer Research Center (DKFZ); Christian Sutter, University Hospital Heidelberg, Heidelberg; Alfons
Meindl, Klinikumrechts der Isar, Technical University Munich; Nina Ditsch, Ludwig-Maximilian University, Munich; Andrea Gehrig,
University Wu¨rzburg, Wu¨rzburg; Bernd Dworniczak, University of Mu¨nster, Mu¨nster; Christoph Engel, University of Leipzig; Dorothea
Wand, University Hospital, Leipzig; Dieter Niederacher, University Hospital Du¨sseldorf, Heinrich-Heine University, Du¨sseldorf; Doris
Steinemann, Hannover Medical School, Hannover; Eric Hahnen, Jan Hauke, Kerstin Rhiem, Barbara Wappenschmidt, and Rita K.
Schmutzler, University Hospital Cologne, Cologne; Karin Kast, University Hospital Carl Gustav Carus, Technical University Dresden,
Dresden; Norbert Arnold, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Kiel; Shan Wang-Gohrke,
University Hospital Ulm, Ulm, Germany; Christine Lasset, Francesca Damiola, and Laure Barjhoux, Centre Le´on Be´rard; Sylvie
Mazoyer, University of Lyon, Lyon;Dominique Stoppa-Lyonnet andMuriel Belotti, Institut Curie, Paris, France;Mattias VanHeetvelde,
Bruce Poppe, Kim De Leeneer, and Kathleen B.M. Claes, Ghent University, Gent, Belgium; Johanna I. Kiiski, Sofia Khan, and Heli
Nevanlinna, University of Helsinki; Johanna I. Kiiski, Kristiina Aittoma¨ki, Sofia Khan, and Heli Nevanlinna, Helsinki University
Hospital, Helsinki, Finland; Christi J. van Asperen, Leiden University Medical Center, Leiden, the Netherlands; Tibor Vaszko, Miklos
Kasler, and Edith Olah, National Institute of Oncology, Budapest, Hungary; Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th.
Johannsson, and Rosa B. Barkardottir, Landspitali University Hospital and Biomedical Centre, University of Iceland, Reykjavik, Iceland;
Manuel R. Teixeira and Pedro Pinto, Portuguese Oncology Institute; Manuel R. Teixeira, Porto University, Porto, Portugal; Jong Won
Lee, Ulsan College ofMedicine and AsanMedical Center;MinHyuk Lee and Jihyoun Lee, Soonchunhyang University andHospital; Sung-
WonKim and Eunyoung Kang, Daerim StMary’s Hospital; Sue Kyung Park, Seoul National University College of Medicine, Seoul; Zisun
Kim, Soonchunhyang University Bucheon Hospital, Bucheon, Korea; Yen Y. Tan, Andreas Berger, and Christian F. Singer, Medical
University of Vienna, Vienna, Austria; Sook-Yee Yoon and Soo-Hwang Teo, Sime DarbyMedical Centre, Subang Jaya,Malaysia; andAnna
von Wachenfeldt, Karolinska University Hospital, Stockholm, Sweden.
Support
Supported by the Italian Association for Cancer Research [AIRC, IG16933; for genotyping of the OncoArray in male mutation
carriers]; genotyping of the OncoArray in CIMBA was supported by the Ministe`re de l’E´conomie, Innovation et Exportation du Que´bec
Grant No. PSR-SIIRI-701 and the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-
129344), the Ministe`re de l’E´conomie, de la Science et de l’Innovation du Que´bec through Genome Que´bec, the Quebec Breast Cancer
2248 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH; Grant No. 1U19-CA148065 for the Discovery,
Biology and Risk of Inherited Variants in Breast Cancer [DRIVE] project; Grant No. X01-HG007492 to the Centre for Inherited Disease
Research), Cancer Research UK (C1287/A16563), Odense University Hospital Research Foundation (Denmark), the National R&D
Program for Cancer Control, Ministry of Health and Welfare (Republic of Korea) (1420190), the Breast Cancer Research Foundation, the
National Health andMedical Research Council (Australia), and German Cancer Aid (110837); CIMBA data management and data analysis
were supported by Cancer Research UKGrants No. C12292/A20861 and C12292/A11174. A.C.A. is a Cancer Research UK Senior Cancer
Research Fellow; G.C.-T. is an NHMRC Senior Principal Research Fellow; J.L. has been financially supported by the Fondation ARC Grant
No. SAE20131200623; the PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the
Canadian Institutes of Health Research, the Ministe`re de l’E´conomie, de la Science et de l’lnnovation du Que´bec through Genome Que´bec,
and the Quebec Breast Cancer Foundation. Also supported by the Ministe`re de l’E´conomie, Innovation et Exportation du Que´bec Grant
No. PSR-SIIRI-701. The Breast Cancer Family Registry (BCFR) was supported by Grant No. UM1-CA164920 from the National Cancer
Institute. BFBOCC-LT (Baltic Familial Breast Ovarian Cancer Consortium Lithuanian section) was supported by Lithuania Research
Council of Lithuania (Grant No. SEN-18/2015). BRICOH (Beckman Research Institute of the City of Hope) S.L.N. is partially supported
by the Morris and Horowitz Families Professorship. CNIO (Spanish National Cancer Centre) was partially supported by Spanish As-
sociation against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA), and SAF2010-20493.
A.O. is supported by SpanishMinistry of Economy and Competitiveness (MINECO) SAF2014-57680-R. The City of Hope Clinical Cancer
Genomics Community Research Network (COH-CCGCRN) was supported in part by Grant No. RC4CA153828 (principal investigator,
J.W.) from the National Cancer Institute and the Office of the Director, NIH. The CONSIT team was supported by the Italian Association
of Cancer Research to P.P. (IG12821), P.R. (IG15547), and L.O. (IG16933), and from Italian citizens who allocated the 53 1,000 share of
their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic
projects “5x1000”) to S.M. Supported by Sapienza University of Rome (post-doc annual research grant “Avvio alla ricerca” 2016) to V.S.
Supported by the ITT (Istituto Toscano Tumori) triennal grant 2010 to D.P. DEMOKRITOS was supported by the European Union
(European Social Fund) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National
Strategic Reference Framework Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA.
Investing in knowledge society through the European Social Fund. The DKFZ study was supported by the DKFZ. EMBRACE was
supported by Cancer Research UKGrants No. C1287/A10118 and C1287/A11990. D.G.E. is supported by an NIH Research (NIHR) grant
to the Biomedical Research Centre, Manchester. The investigators at The Institute of Cancer Research and The Royal Marsden NHS
Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal
Marsden NHS Foundation Trust. R.E. is supported by Cancer Research UK Grant No. C5047/A8385. R.E. is also supported by NIHR
support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC
(Fox Chase Cancer Center) is supported by The University of Kansas Cancer Center (Grant No. P30-CA168524) and the Kansas Bioscience
Authority Eminent Scholar Program. A.K.G. was funded by Grants No. 5U01-CA113916 and R01-CA140323, and by the Chancellors
Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-
HBOC) was supported by the German Cancer Aid (Grant No. 110837; to R.K.S.). GEMO (Genetic Modifiers of cancer risk in BRCA1/2
mutation carriers) was supported by the Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award; the
Canadian Institutes of Health Research for the “CIHRTeam in Familial Risks of Breast Cancer” program and the French National Institute
of Cancer. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: National Cancer Genetics Network
UNICANCERGenetic Group, France. Ghent University Hospital (G-FAST): M.V.H. obtained funding from IWT. HCSC (Hospital Clinico
San Carlos) was supported by Grants No. RD12/00369/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional
Development FEDER funds. HEBCS (Helsinki Breast Cancer Study) was supported by the Helsinki University Hospital Research Fund,
Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. The HEBON study is supported by the
Dutch Cancer Society Grants No. NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research
Grant No. NWO 91109024, the Pink Ribbon Grants No. 110005 and 2014-187.WO76, the BBMRI Grant No. NWO 184.021.007/CP46 and
the Transcan grant JTC 2012 Cancer 12-054. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian
Research Grants No. KTIA-OTKA CK-80745 and OTKA K-112228. HVH (University Hospital Vall d’Hebron) was supported by Spanish
Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European
Regional Development FEDER Funds: FIS PI12/02585 to O.D. and FIS PI13/01711 to S.G.-E. S.G.-E. is funded by Miguel Servet contract
(ISCiii). ICO (Institut Catala` d’Oncologia) contract grant sponsor: Asociacio´n Española Contra el Ca´ncer, Spanish Health Research Fund;
Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; Contract Grants No.: ISCIIIRETIC RD06/
0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The ILUH group was
supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund.
INHERIT (INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility) was supported by the Canadian Institutes of
Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program Grant No. CRN-87521 and the Ministry of Economic
Development, Innovation and Export Trade Grant No. PSR-SIIRI-701. IOVHBOCS (Istituto Oncologico Veneto Hereditary Breast and
Ovarian Cancer Study) was supported by Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. IPOBCS (Portuguese
jco.org © 2017 by American Society of Clinical Oncology 2249
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Oncology Institute-Porto Breast Cancer Study) was supported by Liga Portuguesa Contra o Cancro. kConFab (Kathleen Cuningham
Consortium for Research into Familial Breast Cancer) was supported by a grant from the National Breast Cancer Foundation, and
previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New
South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The Clinical Follow Up Study
received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the US NIH. A.B.S. is supported by an
NHMRC senior research Fellowship (APP1061779). Curation of CIMBAvariant nomenclature and classification in the Spurdle laboratory
was supported by funding from the Cancer Council Queensland (APP1086286). KOHBRA (Korean Hereditary Breast Cancer Study) was
supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of
Korea (1020350). KUMC (University of KansasMedical Center) was supported by the University of Kansas Cancer Center (Grant No. P30-
CA168524). MAYO (Mayo Clinic) was supported by NIH Grants No. CA116167, CA128978, and CA176785, a National Cancer Institute
Specialized Program of Research Excellence (SPORE) in Breast Cancer (Grant No. CA116201), a grant from the Breast Cancer Research
Foundation, and a generous gift from the David F. andMargaret T. Grohne Family Foundation. McGill University was supported by Jewish
General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Memorial
Sloan Kettering Cancer Center was supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical
Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NCI research of M.H.G. and J.T.L was supported by the Intramural
Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with
Westat, Rockville, MD. OSUCCG (The Ohio State University Comprehensive Cancer Center) was supported by the Ohio State University
Comprehensive Cancer Center. SEABASS (South East Asian Breast Cancer Association Study) was supported by the Ministry of Science,
Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. The
Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology, and Innovation,
Ministry of Higher Education (UM.C/HIR/MOHE/06), and charitable funding from Cancer Research Initiatives Foundation. SWE-BRCA
(Swedish Breast Cancer Study) collaborators are supported by the Swedish Cancer Society. University of Chicago was supported by
National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), Grants No. R01-CA142996
and 1U01-CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s
Cancer Research Alliance, and the Breast Cancer Research Foundation. University of Pennsylvania was supported by Breast Cancer
Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. University of Pittsburg Magee-
Women’s Hospital was supported by Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope
Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG) was supported by Victorian Cancer Agency, Cancer Australia, National
Breast Cancer Foundation.
Prior Presentation
Presented at the 2015 Annual Meeting of the American Society of Human Genetics, October 6-10, 2015, Baltimore, MD.
n n n
2250 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Julie Lecarpentier
No relationship to disclose
Valentina Silvestri
No relationship to disclose
Karoline B. Kuchenbaecker
No relationship to disclose
Daniel Barrowdale
Stock or Other Ownership: GlaxoSmithKline
Joe Dennis
No relationship to disclose
Lesley McGuffog
No relationship to disclose
Penny Soucy
No relationship to disclose
Goska Leslie
No relationship to disclose
Piera Rizzolo
No relationship to disclose
Anna Sara Navazio
No relationship to disclose
Virginia Valentini
No relationship to disclose
Veronica Zelli
No relationship to disclose
Andrew Lee
No relationship to disclose
Ali Amin Al Olama
No relationship to disclose
Jonathan P. Tyrer
No relationship to disclose
Melissa Southey
No relationship to disclose
Esther M. John
No relationship to disclose
Thomas A. Conner
No relationship to disclose
David E. Goldgar
No relationship to disclose
Saundra S. Buys
No relationship to disclose
Ramunas Janavicius
No relationship to disclose
Linda Steele
No relationship to disclose
Yuan Chun Ding
No relationship to disclose
Susan L. Neuhausen
No relationship to disclose
Thomas V.O. Hansen
No relationship to disclose
Ana Osorio
No relationship to disclose
Jeffrey N. Weitzel
No relationship to disclose
Angela Toss
No relationship to disclose
Veronica Medici
No relationship to disclose
Laura Cortesi
No relationship to disclose
Ines Zanna
No relationship to disclose
Domenico Palli
No relationship to disclose
Paolo Radice
No relationship to disclose
Siranoush Manoukian
No relationship to disclose
Bernard Peissel
No relationship to disclose
Jacopo Azzollini
No relationship to disclose
Alessandra Viel
No relationship to disclose
Giulia Cini
No relationship to disclose
Giuseppe Damante
No relationship to disclose
Stefania Tommasi
No relationship to disclose
Paolo Peterlongo
No relationship to disclose
Florentia Fostira
No relationship to disclose
Ute Hamann
No relationship to disclose
D. Gareth Evans
Honoraria: AstraZeneca
Alex Henderson
Honoraria: Novartis
Carole Brewer
No relationship to disclose
jco.org © 2017 by American Society of Clinical Oncology
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Diana Eccles
Honoraria: AstraZeneca
Consulting or Advisory Role: AstraZeneca
Jackie Cook
No relationship to disclose
Kai-ren Ong
No relationship to disclose
Lisa Walker
No relationship to disclose
Lucy E. Side
No relationship to disclose
Mary E. Porteous
No relationship to disclose
Rosemarie Davidson
No relationship to disclose
Shirley Hodgson
No relationship to disclose
Debra Frost
No relationship to disclose
Julian Adlard
No relationship to disclose
Louise Izatt
No relationship to disclose
Ros Eeles
No relationship to disclose
Steve Ellis
No relationship to disclose
Marc Tischkowitz
No relationship to disclose
Andrew K. Godwin
Research Funding: Deciphera Pharmaceuticals (Inst)
Alfons Meindl
No relationship to disclose
Andrea Gehrig
No relationship to disclose
Bernd Dworniczak
No relationship to disclose
Christian Sutter
No relationship to disclose
Christoph Engel
No relationship to disclose
Dieter Niederacher
No relationship to disclose
Doris Steinemann
No relationship to disclose
Eric Hahnen
Consulting or Advisory Role: AstraZeneca
Jan Hauke
No relationship to disclose
Kerstin Rhiem
Consulting or Advisory Role: AstraZeneca
Karin Kast
Honoraria: Astra Zeneca
Consulting or Advisory Role: Roche
Travel, Accommodations, Expenses: Celgene, Roche
Norbert Arnold
Honoraria: AstraZeneca
Consulting or Advisory Role: AstraZeneca
Nina Ditsch
No relationship to disclose
Shan Wang-Gohrke
No relationship to disclose
Barbara Wappenschmidt
No relationship to disclose
Dorothea Wand
No relationship to disclose
Christine Lasset
No relationship to disclose
Dominique Stoppa-Lyonnet
Consulting or Advisory Role: AstraZeneca
Research Funding: AstraZeneca (Inst)
Muriel Belotti
No relationship to disclose
Francesca Damiola
No relationship to disclose
Laure Barjhoux
No relationship to disclose
Sylvie Mazoyer
No relationship to disclose
Mattias Van Heetvelde
No relationship to disclose
Bruce Poppe
No relationship to disclose
Kim De Leeneer
No relationship to disclose
Kathleen B.M. Claes
No relationship to disclose
Miguel de la Hoya
No relationship to disclose
Vanesa Garcia-Barberan
No relationship to disclose
Trinidad Caldes
No relationship to disclose
Pedro Perez Segura
No relationship to disclose
Johanna I. Kiiski
No relationship to disclose
Kristiina Aittoma¨ki
No relationship to disclose
Sofia Khan
No relationship to disclose
Heli Nevanlinna
No relationship to disclose
© 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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Christi J. van Asperen
Research Funding: AstraZeneca (Inst)
Tibor Vaszko
No relationship to disclose
Miklos Kasler
No relationship to disclose
Edith Olah
No relationship to disclose
Judith Balmaña
No relationship to disclose
Sara Gutie´rrez-Enrı´quez
No relationship to disclose
Orland Diez
No relationship to disclose
Alex Teule´
No relationship to disclose
Angel Izquierdo
No relationship to disclose
Esther Darder
No relationship to disclose
Joan Brunet
No relationship to disclose
Jesu´s Del Valle
Speakers’ Bureau: AstraZeneca
Lidia Feliubadalo
Speakers’ Bureau: AstraZeneca
Miquel Angel Pujana
Research Funding: Roche (Inst), Astellas Pharma (Inst)
Conxi Lazaro
No relationship to disclose
Adalgeir Arason
No relationship to disclose
Bjarni A. Agnarsson
No relationship to disclose
Oskar Th. Johannsson
Consulting or Advisory Role: Tesaro
Travel, Accommodations, Expenses: Roche, Novartis
Rosa B. Barkardottir
No relationship to disclose
Elisa Alducci
No relationship to disclose
Silvia Tognazzo
No relationship to disclose
Marco Montagna
No relationship to disclose
Manuel R. Teixeira
No relationship to disclose
Pedro Pinto
No relationship to disclose
Amanda B. Spurdle
No relationship to disclose
Helene Holland
No relationship to disclose
Jong Won Lee
No relationship to disclose
Min Hyuk Lee
No relationship to disclose
Jihyoun Lee
No relationship to disclose
Sung-Won Kim
No relationship to disclose
Eunyoung Kang
No relationship to disclose
Zisun Kim
No relationship to disclose
Priyanka Sharma
Consulting or Advisory Role: Abbvie
Research Funding: GlaxoSmithKline, Novartis, Celgene, Cosmo
Biosciences (I)
Travel, Accommodations, Expenses: Abbvie
Timothy R. Rebbeck
No relationship to disclose
Joseph Vijai
No relationship to disclose
Mark Robson
Honoraria: AstraZeneca
Consulting or Advisory Role: McKesson, AstraZeneca
Research Funding: AstraZeneca (Inst), AbbVie (Inst), Myriad Genetics
(Inst), Medivation (Inst), Tesaro (Inst)
Travel, Accommodations, Expenses: AstraZeneca
Anne Lincoln
No relationship to disclose
Jacob Musinsky
No relationship to disclose
Pragna Gaddam
No relationship to disclose
Yen Y. Tan
No relationship to disclose
Andreas Berger
No relationship to disclose
Christian F. Singer
No relationship to disclose
Jennifer T. Loud
No relationship to disclose
Mark H. Greene
No relationship to disclose
Anna Marie Mulligan
No relationship to disclose
Gord Glendon
No relationship to disclose
Irene L. Andrulis
No relationship to disclose
Amanda Ewart Toland
No relationship to disclose
jco.org © 2017 by American Society of Clinical Oncology
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
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Leigha Senter
Consulting or Advisory Role: Clovis Oncology, MyGeneCounsel
Anders Bojesen
No relationship to disclose
Henriette Roed Nielsen
No relationship to disclose
Anne-Bine Skytte
No relationship to disclose
Lone Sunde
No relationship to disclose
Uffe Birk Jensen
No relationship to disclose
Inge Sokilde Pedersen
No relationship to disclose
Lotte Krogh
No relationship to disclose
Torben A. Kruse
No relationship to disclose
Maria A. Caligo
No relationship to disclose
Sook-Yee Yoon
Research Funding: AstraZeneca
Soo-Hwang Teo
Honoraria: AstraZeneca
Consulting or Advisory Role: AstraZeneca
Research Funding: AstraZeneca (Inst)
Anna von Wachenfeldt
No relationship to disclose
Dezheng Huo
No relationship to disclose
Sarah M. Nielsen
No relationship to disclose
Olufunmilayo I. Olopade
No relationship to disclose
Katherine L. Nathanson
No relationship to disclose
Susan M. Domchek
Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst), AbbVie
(Inst), PharmaMar (Inst)
Christa Lorenchick
No relationship to disclose
Rachel C. Jankowitz
Consulting or Advisory Role: Advaxis, bioTheranostics
Ian Campbell
No relationship to disclose
Paul James
No relationship to disclose
Gillian Mitchell
Honoraria: AstraZeneca
Consulting or Advisory Role: AstraZeneca
Travel, Accommodations, Expenses: AstraZeneca
Nick Orr
No relationship to disclose
Sue Kyung Park
No relationship to disclose
Mads Thomassen
No relationship to disclose
Kenneth Offit
No relationship to disclose
Fergus J. Couch
Travel, Accommodations, Expenses: Ambry Genetics
Jacques Simard
No relationship to disclose
Douglas F. Easton
No relationship to disclose
Georgia Chenevix-Trench
No relationship to disclose
Rita K. Schmutzler
No relationship to disclose
Antonis C. Antoniou
No relationship to disclose
Laura Ottini
No relationship to disclose
© 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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Acknowledgment
We thank Sue Healey for her contribution to CIMBA, in particular, for taking on the task of mutation classification with Olga Sinilnikova.
BCFR Australia: We acknowledge Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR Ontario: We thank members and
participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT (Baltic Familial Breast Ovarian
Cancer Consortium Lithuanian section): We acknowledge Vilius Rudaitis and Laimonas Grisˇkevicˇius. CBCS (Copenhagen Breast Cancer
Study, Rigshospitalet): We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of
participants. CNIO (Spanish National Cancer Centre): We thank Alicia Barroso, Rosario Alonso, and Guillermo Pita for their assistance.
COH-CCGCRN (City of Hope Clinical Cancer Genomics Community Research Network): Patients were recruited for study from the City
of Hope Clinical Cancer Genomics Community Research Network. CONSIT TEAM: We acknowledge Daniela Zaffaroni of the Fondazione
IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II”, Bari, Italy; and
the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FCCC (Fox Chase Cancer Center): We thank Jo Ellen Weaver
and Betsy Bove, MD, for their technical support.GEMO (Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers): We pay a tribute
to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet, initiated and coordinated GEMO until she died on June 30, 2014, and we
thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres,
Unite´ Mixte de Ge´ne´tique Constitutionnelle des Cancers Fre´quents, Hospices Civils de Lyon–Centre Le´on Be´rard, Equipe Ge´ne´tique du
cancer du sein, Centre de Rechercheen Cance´rologie de Lyon: Olga Sinilnikova (deceased), Sylvie Mazoyer, Francesca Damiola, Laure
Barjhoux, Carole Verny-Pierre, Me´lanie Le´one, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Ge´ne´tique
Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne
Rouleau, Lisa Golmard, Agne`s Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues,
Emmanuelle Fourme, Anne-Marie Birot; Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-
Bataille; Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer; Centre Le´on Be´rard, Lyon: Christine Lasset,
Vale´rie Bonadona, Sandrine Handallou; Centre François Baclesse, Caen: Agne`s Hardouin, Pascaline Berthet, Dominique Vaur, Laurent
Castera; Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger;
CHUArnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol; Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joe¨lle Fournier,
Françoise Re´villion, Philippe Vennin (deceased), Claude Adenis; Centre Paul Strauss, Strasbourg: Danie`le Muller, Jean-Pierre Fricker;
Institut Bergonie´, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy; Institut
Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel; CHU Grenoble: Dominique Leroux,
He´le`ne Dreyfus, Christine Rebischung, Magalie Peysselon; CHU Dijon: Fanny Coron, Laurence Faivre; CHU St-Etienne: Fabienne Prieur,
Marine Lebrun, Caroline Kientz; HoˆtelDieu Centre Hospitalier, Chambe´ry: Sandra Fert Ferrer; Centre Antoine Lacassagne, Nice: Marc
Fre´nay; CHU Limoges: Laurence Ve´nat-Bouvet; CHU Nantes: Capucine Delnatte; CHU Bretonneau, Tours: Isabelle Mortemousque;
Groupe Hospitalier Pitie´-Salpe´trie`re, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin; CHU Vandoeuvre-les-
Nancy: Johanna Sokolowska, Myriam Bronner; CHU Besançon: Marie-Agne`s Collonge-Rame, Alexandre Damette; Creighton University,
Omaha, NE: Henry T. Lynch, Carrie L. Snyder. G-FAST (Ghent University Hospital): B.P. is a senior clinical investigator of FWO. We
acknowledge the technical support of Ilse Coeneen Brecht Crombez. HCSC (Hospital Clinico San Carlos): We acknowledge Alicia Tosar
and Paula Diaque for their technical assistance. HEBCS (Helsinki Breast Cancer Study): We thank Taru A. Muranen, Carl Blomqvist, MD,
Kirsimari Aaltonen, MD, Irja Erkkila¨, RN, and Virpi Palola, RN, for their help with the HEBCS data and samples. Hereditary Breast and
Ovarian Cancer Research Group Netherlands (HEBON): HEBON consists of the following collaborating centers: Coordinating center:
Netherlands Cancer Institute, Amsterdam: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L.
de Lange, R. Wijnands; Erasmus Medical Center: J.M. Colle´e, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van
Deurzen, I.M. Obdeijn; Leiden University Medical Center: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van
Cronenburg; Radboud University Nijmegen Medical Center: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht: M.G.E.M.
Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center: C.M. Aalfs, T.A.M. van Os; Vrije Universiteit Medical Center:
J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht: E.B. Go´mez-Garcia, M.J. Blok; University Medical Center
Groningen: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary
Tumours, Leiden: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology
Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection.HUNBOCS
(Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary): We thank the Hungarian Breast and Ovarian Cancer Study Group
members (Janos Papp, Aniko Bozsik, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics,
National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH (University
Hospital Vall d’Hebron): We thank the Cellex Foundation for providing research facilities and equipment. ICO (Institut Catala`
d’Oncologia): We thank the ICO Hereditary Cancer Program team led by Gabriel Capella, MD. INHERIT (INterdisciplinary HEalth
Research Internal Team BReast CAncer susceptibility): We thank Martine Dumont, MD, Martine Tranchant and Ste´phane Dubois for QC,
sample management and skillful assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the
QC and Genotyping coordinating group of iCOGS and Oncoarray (BCAC and CIMBA). IPOBCS (Portuguese Oncology Institute-Porto
jco.org © 2017 by American Society of Clinical Oncology
Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Breast Cancer Study): We thank Catarina Santos, MD, for her skillful contribution to the study. kConFab (Kathleen Cuningham
Consortium for Research into Familial Breast Cancer): We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses
and staff, the heads and staff of the Family Cancer Clinics, and the Clinical FollowUp Study for their contributions to this resource, and the
many families who contribute to kConFab.Memorial Sloan Kettering Cancer Center: We acknowledge Lauren Jacobs, MD.OCGN (Ontario
Cancer Genetics Network): We thank members and participants in the Ontario Cancer Genetics Network for their contributions to the
study. OSUCCG (The Ohio State University Comprehensive Cancer Center): Kevin Sweet, Caroline Craven, Julia Cooper, Leigha Senter,
and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records, and database management.
SEABASS (South East Asian Breast Cancer Association Study): We thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee,
Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient
recruitment, data collection, and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for
contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively. SWE-BRCA (Swedish Breast
Cancer Study): Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: A˚ke Borg,
Ha˚kan Olsson, Helena Jernstro¨m, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska
University Hospital: Anna O¨fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University
Hospital: Anna vonWachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umea˚
University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona,
Maritta Hellstro¨m Pigg, Richard Rosenquist; from Linko¨ping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. University
of Chicago: O.I.O. is an ACS Clinical Research Professor. We thank Cecilia Zvocec, Qun Niu, physicians, genetic counsellors, research
nurses, and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program.
VFCTG (Victorian Familial Cancer Trials Group): We acknowledge Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian
Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing
all DNA amplification.
© 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Lecarpentier et al
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