00 MONTH 2017 | VOL 000 | NATURE | 1
LETTER
doi:10.1038/nature24284
Association analysis identifies 65 new breast cancer
risk loci
Lists of authors and their affiliations appear in the online version of the paper
Breast cancer risk is influenced by rare coding variants in
susceptibility genes, such as BRCA1, and many common, mostly
non-coding variants. However, much of the genetic contribution to
breast cancer risk remains unknown. Here we report the results of
a genome-wide association study of breast cancer in 122,977 cases
and 105,974 controls of European ancestry and 14,068 cases and
13,104 controls of East Asian ancestry
1
. We identified 65 new loci
that are associated with overall breast cancer risk at P < 5 × 10
−8
.
The majority of credible risk single-nucleotide polymorphisms in
these loci fall in distal regulatory elements, and by integrating in
silico data to predict target genes in breast cells at each locus, we
demonstrate a strong overlap between candidate target genes and
somatic driver genes in breast tumours. We also find that heritability
of breast cancer due to all single-nucleotide polymorphisms in
regulatory features was 2–5-fold enriched relative to the genome-
wide average, with strong enrichment for particular transcription
factor binding sites. These results provide further insight into
genetic susceptibility to breast cancer and will improve the use of
genetic risk scores for individualized screening and prevention.
We genotyped 61,282 female cases with breast cancer and 45,494
female controls of European ancestry using the OncoArray
1
. Subjects
came from 68 studies collaborating in the Breast Cancer Association
Consortium (BCAC) and Discovery, Biology and Risk of Inherited
Variants in Breast Cancer Consortium (DRIVE) (Supplementary
Table 1). Using the 1000 Genomes Project (phase 3) reference panel,
we imputed genotypes for approximately 21 million variants. After
filtering for a minor allele frequency of less than 0.5% and imputation
quality score of less than 0.3 (see Methods), we assessed the associ-
ation between breast cancer risk and 11.8 million single-nucleotide
polymorphisms (SNPs) adjusting for country and ancestry-informative
principal components. We combined these results with results from the
Collaborative Oncological Gene-environment Study (iCOGS: 46,785
cases and 42,892 controls)
2
and 11 other breast cancer genome-wide
association studies (GWAS; 14,910 cases and 17,588 controls), using a
fixed-effect meta-analysis.
Of 102 loci that have previously been associated with breast cancer in
Europeans, 49 showed evidence for association with breast cancer in the
OncoArray dataset at P < 5 × 10
−8
and 94 at P < 0.05. Five additional
loci that had previously been shown to be associated with breast cancer
in Asian women
3–5
also showed evidence in the European ancestry
OncoArray dataset (P < 0.01; Supplementary Tables 2–4). We also
assessed the association with breast cancer in Asians, including 7,799
cases and 6,480 controls from the OncoArray project and 6,269 cases
and 6,624 controls from the iCOGS project. Of the 94 loci that had
previously been identified in Europeans that were polymorphic in
Asians, 50 showed evidence of association (P < 0.05). For the remaining
44, none showed a significant difference in the estimated odds ratio
for overall breast cancer risk between Europeans and Asians (P > 0.01;
Supplementary Table 5). The correlation in effect sizes for all known loci
between Europeans and Asians was 0.83, suggesting that the majority
of known susceptibility loci are shared between these populations.
To search for additional susceptibility loci, we assessed all SNPs
excluding those within 500 kb of a known susceptibility SNP
(Fig. 1). This identified 5,969 variants in 65 regions that were associated
with overall breast cancer risk at P < 5 × 10
−8
(Supplementary
Tables 6–8). For two loci (lead SNPs rs58847541 and rs12628403), there
was evidence of a second association signal after adjustment for the
primary signal (rs13279803: conditional P = 1.6 × 10
−10
; rs373038216:
P = 2.9 × 10; Supplementary Table 9). Of the 65 new loci, 21 showed a dif-
ferential association based on oestrogen receptor (ER) status (P < 0.05),
with all but two SNPs (rs6725517 and rs6569648) more strongly
associated with ER-positive disease (Supplementary Tables 10, 11).
Forty-four loci showed evidence of association with ER-negative breast
cancer (P < 0.05). Of the 51 novel loci that were polymorphic in Asians,
300
a
b
250
200
150
35
30
25
20
15
10
5
0
100
50
0
123
–log
10
(P)–log
10
(P)
456789 11 13 15 18 21
123456789
Chromosome
11 13 15 18 21
Figure 1 | SNP associations with breast cancer risk. a, Manhattan plot
showing − log
10
P values for SNP associations with breast cancer risk.
b, Manhattan plot after excluding previously identified associated regions.
The red line denotes ‘genome-wide’ significance (P < 5 × 10
−8
); the blue
line denotes P < 10
−5
.
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
2 | NATURE | VOL 000 | 00 MONTH 2017
Letter
reSeArCH
nine were associated at P < 0.05 and only two showed a difference in
the estimated odds ratio between Europeans and Asians (P < 0.01;
Supplementary Table 12).
To define a set of credible risk variants (CRVs) at the new loci,
we first selected variants with P values within two orders of magni
-
tude of the most significant SNPs in each region. Across the 65 novel
regions, we identified 2,221 CRVs (Supplementary Table 13), while
the 77 previously identified loci contained 2,232 CRVs (Methods and
Supplementary Table 14). We examined these CRVs for evidence of
enrichment of 67 genomic features, including histone markers and
transcription factor binding sites in three breast cancer cell lines
(Methods, Extended Data Fig. 1 and Supplementary Tables 15, 16).
Thirteen features were significant predictors of CRVs at P < 10
−4
;
the strongest were DNase I hypersensitivity sites in CTCF-silenced
MCF7 cells (odds ratio = 2.38, P = 4.6 × 10
−14
). Strong associations
were also observed at binding sites for FOXA1, ESR1, GATA3, E2F1
and TCF7L2. In addition, 7 of the 65 novel loci included only a single
CRV (Supplementary Table 6), of which two were non-synonymous.
SNP rs16991615 is a missense variant (p.Glu341Lys) in MCM8, which
is involved in genome replication and associated with age at natural
menopause and impaired DNA repair
6
. SNP rs35383942 is a missense
variant (p.Arg28Gln) in PHLDA3, encoding a p53-regulated repressor
of AKT
7
.
We annotated each CRV with publicly available genomic data
from breast cells in order to highlight potentially functional variants,
predict target genes and prioritize future experimental validation
(Supplementary Tables 7, 13 with UCSC (University of California Santa
Cruz) browser links). We developed a heuristic scoring system based
on breast-specific genomic data (integrated expression quantitative
trait and in silico prediction of GWAS targets (INQUISIT)) to rank
the target genes at each locus (Supplementary Table 17). Target genes
were predicted by combining risk SNP data with multiple sources of
genomic information, including chromatin interactions (chromatin
interaction analysis by paired-end tag sequencing (ChIA-PET) and
genome-wide chromosome conformation capture (Hi-C)), compu-
tational enhancer–promoter correlations (PreSTIGE (ref. 8), IM-PET
(ref. 9), FANTOM5 (ref. 10) and super-enhancers), results for breast
tissue-specific expression quantitative trait loci (eQTLs), transcription
factor binding (ENCODE (Encyclopedia of DNA Elements) chromatin
immunoprecipitation followed by sequencing (ChIP–seq)), gene
expression (ENCODE RNA sequencing (RNA-seq)) and topologically
associated domain boundaries (Methods and Supplementary Tables
18–20). Target gene predictions could be made for 58 out of 65 new and
70 out of 77 previously identified loci. Among 689 protein-coding genes
predicted by INQUISIT, we found strong enrichment for esta blished
breast cancer drivers identified through tumour sequencing (20 out of
147 genes, P < 10
−6
)
11–14
, which increased with increasing INQUISIT
score (P = 1.8 × 10
−6
). We compared INQUISIT with two alterna-
tive methods. Firstly, an alternative, published method (Data-driven
Expression-Prioritized Integration for Complex Traits (DEPICT),
which predicts targets based on shared gene functions between
potential targets at other associated loci)
15
showed a weaker enrich-
ment of breast cancer driver genes (P = 0.06 after adjusting for the
nearest gene, P = 0.74 after adjusting for INQUISIT score). Secondly,
after assigning the association signal to the nearest gene, only a weak
enrichment of driver genes after adjusting for the INQUISIT score was
found (P = 0.01; Extended Data Table 1 and Supplementary Table 21).
Notably, most of the 689 putative target genes have no reported involve-
ment in breast tumorigenesis and some may represent additional genes
that influence the susceptibility to breast cancer. However, functional
assays will be required to confirm whether any of these candidate genes
is causally implicated in breast cancer susceptibility.
Having used INQUISIT to predict target genes, we performed
pathway gene set enrichment analysis, the results of which are
visually summarized as enrichment maps
16
(Extended Data Fig. 2
and Supplementary Tables 22, 23). Several growth or development
related pathways were enriched, notably the fibroblast growth factor,
platelet-derived growth factor and Wnt signalling pathways
17–19
. Other
cancer-related themes included ERK1/2 cascade, immune- response
pathways, including interferon signalling, and cell-cycle pathways.
Pathways that were not found in earlier breast cancer GWAS include
nitric-oxide biosynthesis, AP-1 transcription factor and NF-κ B
(Supplementary Table 24).
To explore more globally the genomic features that contribute to
breast cancer risk, we estimated the proportion of genome-wide SNP
heritability attributable to 53 publicly available annotations
20
. We
observed the largest enrichment in heritability (5.2-fold, P = 8.5 × 10
−5
)
of transcription factor binding sites, followed by a fourfold (P = 0.0006)
enrichment of histone marker H3K4me3 (marking promoters). By
contrast, we observed a significant depletion (0.27, P = 0.0007) in
repressed regions (Supplementary Table 25). We conducted cell-type-
specific enrichment analysis for four histone markers and observed
significant enrichments in several tissue types (Extended Data Figs 3–7
and Supplementary Table 26, 27), including a 6.7-fold enrichment of
H3K4me1 in breast myoepithelial tissue (P = 7.9 × 10
−5
). We compared
the cell-type-specific enrichments for all, ER-positive and ER-negative
breast cancers to the enrichments for 16 other complex traits (Extended
Data Figs 3–7). Breast cancer showed enrichment in adipose and
epithelial cell types (including breast epithelial cells). By contrast,
psychiatric diseases showed enrichment specific to cell types of the
central nervous system and autoimmune disorders showed enrichment
in immune cells.
We selected four loci for further evaluation to represent those
that are predicted to act through proximal regulation (1p36 and
11p15) and distal regulation (1p34 and 7q22), because they had
a relatively small number of CRVs. Firstly, the only CRV at 1p36,
rs2992756 (P = 1.6 × 10
−15
), is located 84bp from the transcription
start site of KLHDC7A. Secondly, of the 19 CRVs at 11p15 (smallest
P = 1.4 × 10
−12
), five were located in the proximal promoter of PIDD1,
which is implicated in DNA-damage-induced apoptosis and tumor-
igenesis
21
. INQUISIT predicted KLHDC7A and PIDD1 to be target
genes and these genes had the highest score for the likelihood of
promoter regulation (Supplementary Table 19). Using reporter assays,
we showed that the KLHDC7A promoter construct containing the risk
T-allele of rs2992756 has significantly lower activity than the reference
construct, while the PIDD1 promoter construct containing the risk
haplotype significantly increased PIDD1 promoter activity (Extended
Data Fig. 8).
Thirdly, the 1p34 locus included four CRVs (smallest P = 9.1 × 10
−9
)
that are within two putative regulatory elements (PREs) and are
predicted by INQUISIT to regulate CITED4 (Extended Data Fig. 8).
CITED4 encodes a transcriptional coactivator that interacts with
CBP, p300 and TFAP2 and can inhibit hypoxia-activated transcrip
-
tion in cancer cells
22
. Chromatin conformation capture assays con-
firmed that the PREs physically interacted with the CITED4 promoter
(Extended Data Fig. 8). Subsequent reporter assays showed that the
PRE1 reference construct reduced CITED4 promoter activity, whereas
the risk T-allele of SNP rs4233486 located in PRE1 negates this effect.
Finally, the 7q22 risk locus contained six CRVs (smallest
P = 5.1 × 10
−12
) that were found to be in several PREs spanning
around 40 kb of intron 1 of CUX1. Chromatin interactions were iden-
tified between PRE1 (containing SNP rs6979850) and the promoters
of CUX1 and RASA4 and between PRE2 (containing SNP rs71559437)
and the promoters of RASA4 and PRKRIP1 (Extended Data Fig. 9).
Allele-specific chromatin conformation capture assays in hetero zygous
MBA-MB-231 cells showed that the risk haplotype was associated
with chromatin looping, suggesting that the protective allele abrogates
looping between the PREs and target genes (Extended Data Fig. 9).
These results identify two mechanisms by which CRVs may affect target
gene expression: through transactivation of a specific promoter and
by affecting chromatin looping between regulatory elements and their
target genes. These data provide in vitro evidence of target identification
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
00 MONTH 2017 | VOL 000 | NATURE | 3
Letter
reSeArCH
and regulation; however further studies that include genome editing,
oncogenic assays and/or animal models will be required to fully eluci-
date disease-related gene function.
We estimate that the newly identified susceptibility loci explain
around 4% of the twofold familial relative risk of breast cancer and
that in total, common susceptibility variants identified through GWAS
explain 18% of the familial relative risk. Furthermore, we estimate that
variants that can be reliably imputed using the OncoArray explain
around 41% of the familial relative risk, assuming a log-additive model
(see Methods). Therefore, the identified susceptibility SNPs account
for around 44% (18% out of 41%) of the familial relative risk that can
be explained by all imputable SNPs. The identified SNPs will be incor-
porated into risk prediction models, which can be used to improve the
identification of women that are at high or low risk of breast cancer:
for example, using a polygenic risk score based on the variants that
have been identified to date, women in the highest 1% of the distribu-
tion have a 3.5-fold greater risk of breast cancer than the population
average. Such risk prediction can inform targeted early detection and
prevention.
Online Content Methods, along with any additional Extended Data display items and
Source Data, are available in the online version of the paper; references unique to
these sections appear only in the online paper.
Received 21 June 2016; accepted 17 September 2017.
Published online 23 October 2017.
1. Amos, C. I. et al. The OncoArray Consortium: a network for understanding the
genetic architecture of common cancers. Cancer Epidemiol. Biomarkers Prev.
26, 126–135 (2017).
2. Michailidou, K. et al. Large-scale genotyping identies 41 new loci associated
with breast cancer risk. Nat. Genet. 45, 353–361 (2013).
3. Long, J. et al. Genome-wide association study in East Asians identies novel
susceptibility loci for breast cancer. PLoS Genet. 8, e1002532 (2012).
4. Cai, Q. et al. Genome-wide association analysis in East Asians identies breast
cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat. Genet. 46,
886–890 (2014).
5. Long, J. et al. A common deletion in the APOBEC3 genes and breast cancer
risk. J. Natl Cancer Inst. 105, 573–579 (2013).
6. He, C. et al. Genome-wide association studies identify loci associated with age
at menarche and age at natural menopause. Nat. Genet. 41, 724–728
(2009).
7. Kawase, T. et al. PH domain-only protein PHLDA3 is a p53-regulated repressor
of Akt. Cell 136, 535–550 (2009).
8. Corradin, O. et al. Combinatorial eects of multiple enhancer variants in
linkage disequilibrium dictate levels of gene expression to confer susceptibility
to common traits. Genome Res. 24, 1–13 (2014).
9. He, B., Chen, C., Teng, L. & Tan, K. Global view of enhancer–promoter
interactome in human cells. Proc. Natl Acad. Sci. USA 111, E2191–E2199
(2014).
10. Andersson, R. et al. An atlas of active enhancers across human cell types and
tissues. Nature 507, 455–461 (2014).
11. Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer
whole-genome sequences. Nature 534, 47–54 (2016).
12. Cancer Genome Atlas Network. Comprehensive molecular portraits of human
breast tumours. Nature 490, 61–70 (2012).
13. Ciriello, G. et al. Comprehensive molecular portraits of invasive lobular breast
cancer. Cell 163, 506–519 (2015).
14. Pereira, B. et al. The somatic mutation proles of 2,433 breast cancers rene
their genomic and transcriptomic landscapes. Nat. Commun. 7, 11479
(2016).
15. Pers, T. H. et al. Biological interpretation of genome-wide association studies
using predicted gene functions. Nat. Commun. 6, 5890 (2015).
16. Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: a
network-based method for gene-set enrichment visualization and
interpretation. PLoS ONE 5, e13984 (2010).
17. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to
cancer. Nat. Rev. Cancer 10, 116–129 (2010).
18. Heldin, C. H. Targeting the PDGF signaling pathway in tumor treatment.
Cell Commun. Signal. 11, 97 (2013).
19. Howe, L. R. & Brown, A. M. Wnt signaling and breast cancer. Cancer Biol. Ther.
3, 36–41 (2004).
20. Finucane, H. K. et al. Partitioning heritability by functional annotation using
genome-wide association summary statistics. Nat. Genet. 47, 1228–1235
(2015).
Supplementary Information is available in the online version of the paper.
Acknowledgements We thank all the individuals who took part in these studies
and all the researchers, clinicians, technicians and administrative staff who
have enabled this work to be carried out. Genotyping of the OncoArray was
principally funded from three sources: the PERSPECTIVE project, funded
by the Government of Canada through Genome Canada and the Canadian
Institutes of Health Research, the ‘Ministère de l’Économie, de la Science
et de l’Innovation du Québec’ through Genome Québec, and the Quebec
Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in
Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited
Variants in Breast Cancer (DRIVE) project (NIH Grants U19 CA148065 and
X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/
A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by
the European Community’s Seventh Framework Programme under grant
agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European
Union’s Horizon 2020 Research and Innovation Programme under grant
agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the
iCOGS array was funded by the European Union (HEALTH-F2-2009-223175),
Cancer Research UK (C1287/A10710), the Canadian Institutes of Health
Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and
the Ministry of Economic Development, Innovation and Export Trade of Quebec,
grant PSR-SIIRI-701. Combining of the GWAS data was supported in part by
The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant
U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of
funding and acknowledgments, see Supplementary Note.
Author Contributions Writing group: K.Mi., S.Li., J.Bee., S.Hu., S.Ka., P.So., S.L.E.,
G.D.B., G.C.-T., J.Si., P.K. and D.F.E. Conceived the OncoArray and obtained
financial support: C.I.A., J.Si., P.K. and D.F.E. Designed the OncoArray: J.D., E.D.,
A. Lee, Z.W., A.C.A., C.I.A., S.J.C., P.K. and D.F.E. Led the COGS project: P.Hal. Led
the DRIVE project: D.J.H. Led the PERSPECTIVE project: J.Si. Led the working
groups of BCAC: A.C.A., I.L.A., P.D.P.P., J.C.-C., R.L.M., M.G.-C., M.K.S. and A.M.D.
Data management: J.D., M.K.B., Q.Wan., R.Ke., U.E., S.B., J.C.-C. and M.K.S.
Bioinformatics analysis: J.D., J.Bee., A.Lem., P.So., J.A., M.Gh., J.C., A.D., A.E.M.R.,
S.R.L. Statistical analysis: K.Mi., S.Li., S.Hu., S.Ka., A.Ros., J.T., X.Q.C., L.Fa., X.J.,
H.Fi., G.D.B., P.K. and D.F.E. Functional analysis: D.G., X.Q.C., J.Bee., J.D.F., K.Mc.,
S.L.E. and G.C.-T. OncoArray genotyping: M.A., F.B., C.Ba., D.M.C., J.M.C., K.F.D.,
N.Ha., B.H., K.J., C.L., J.Me., E.P., J.R., G.S., D.C.T., D.V.D.B., D.V., J.V., L.X., B.Z. and
A.M.D. Provided DNA samples and/or phenotypic data: M.A.A., H.A., K.A., H.A.-C.,
N.N.A., V.A., K.J.A., B.A., P.L.A., M.Ba., M.W.B., J.Ben., M.Be., L.Be., C.Bl., N.V.B.,
S.E.B., B.Bo., A.-L.B.-D., J.S.B., H.Bra., P.Bre., H.Bre., L.Br., P.Bro., I.W.B., A.B.,
A.B.-W., S.Y.B., T.B., B.Bu., K.B., H.Ca., Q.C., T.C., F.C., A.Ca., B.D.C., J.E.C., T.L.C.,
T.-Y.D.C., K.S.C., J.-Y.C., H.Ch., C.L.C., M.C., E.C.-D., S.C., A.Co., D.G.C., S.S.C., K.C.,
M.B.D., P.D., T.D., I.d.-S.-S., M.Du., L.D., M.Dw., D.M.E., A.B.E., A.H.E., C.El., M.El.,
C.En., M.Er., P.A.F., J.F., D.F.-J., O.F., H.Fl., L.Fr., V.Ga., M.Ga., M.G.-D., Y.-T.G., S.M.G.,
J.A.G.-S., M.M.G., V.Ge., G.G.G., G.G., M.S.G., D.E.G., A.G.-N., G.I.G.A., M.Gr., J.G.,
A.G., P.G., L.H., E.H., C.A.H., N.Hå., U.H., S.Ha., P.Har., S.N.H., J.M.H., M.H., A.He.,
J.H., P.Hi., D.N.H., A.Ho., M.J.H., R.N.H., J.L.H., M.-F.H., C.-N.H., G.H., K.H., J.I., H.It.,
M.I., H.Iw., A.J., W.J., E.M.J., N.J., M.J., A.J.-V., R.Ka., M.K., K.K., D.K., Y.K., M.J.K.,
S.Kh., E.K., J.I.K., S.-W.K., J.A.K., V.-M.K., I.M.K., V.N.K., U.K., A.K., D.L., L.L.M., C.N.L.,
E.L., J.W.L., M.H.L., F.L., J. Li, J.Lil., A.Li., J.Lis., R.L., W.-Y.L., S.Lo., J.Lo., A.Lo., J.Lu.,
M.P.L., E.S.K.M., R.J.M., T.M., E.M., K.E.M., A.Ma., S.Man., J.E.M., S.Marg., S.Mari.,
M.E.M., K.Ma., D.M., J.Mc., C.Mc., H.M.-H., A.Me., P.M., U.M., H.M., N.M., K.Mu.,
A.M.M., C.Mu., S.L.N., H.N., P.N., S.F.N., D.-Y.N., B.G.N., A.N., O.I.O., J.E.O., H.O.,
C.O., N.O., V.S.P., S.K.P., T.-W.P.-S., J.I.A.P., P.P., J.P., K.-A.P., M.P., D.P.-K., R.P., N.P.,
D.P., K.P., B.R., P.R., N.R., G.R., H.S.R., V.R., A.Rom., K.J.R., T.R., A.Ru., M.R., E.J.T.R.,
E.S., D.P.S., S.Sa., E.J.S., D.F.S., R.K.S., A.Sc., M.J.Sc., F.S., P.Sc., C.Sc., R.J.S., S.Se.,
C.Se., M.S., P.Sh., C.-Y.S., M.E.S., M.J.Sh., X.-O.S., A.Sm., C.So., M.C.S., J.J.S., C.St.,
S.S.-B., J.St., D.O.S., H.S., A.Sw., N.A.M.T., R.T., J.A.T., M.T., S.H.T., M.B.T., S.Th.,
K.T., R.A.E.M.T., I.T., L.T., D.T., T.T., C.-C.T., S.Ts., H.-U.U., M.U., G.U., C.V., C.J.v.A.,
A.M.W.v.d.O., L.v.d.K., R.B.v.d.L., Q.Wai., S.W.-G., C.R.W., C.W., A.S.W., H.W., W.W.,
R.W., A.W., A.H.W., T.Y., X.R.Y., C.H.Y., K.-Y.Y., J.-C.Y., W.Z., Y.Z., A.Z., E.Z., ABCTB
Investigators, kConFab/AOCS Investigators, NBCS Collaborators, A.C.A., I.L.A.,
F.J.C., P.D.P.P., J.C.-C., P.Hal., D.J.H., R.L.M., M.G.-C., M.K.S., G.D.B., J.Si., P.K. and
D.F.E. All authors read and approved the final version of the manuscript.
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Correspondence and requests for materials should be addressed to
D.F.E. (dfe20@medschl.cam.ac.uk).
21. Lin, Y., Ma, W. & Benchimol, S. Pidd, a new death-domain-containing protein, is
induced by p53 and promotes apoptosis. Nat. Genet. 26, 122–127 (2000).
22. Fox, S. B. et al. CITED4 inhibits hypoxia-activated transcription in cancer cells,
and its cytoplasmic location in breast cancer is associated with elevated
expression of tumor cell hypoxia-inducible factor 1α . Cancer Res. 64,
6075–6081 (2004).
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Letter
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KyriakiMichailidou
1,2
*, SaraLindström
3,4
*, JoeDennis
1
*, JonathanBeesley
5
*, ShirleyHui
6
*,
SiddharthaKar
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*, AudreyLemaçon
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, PennySoucy
8
, DylanGlubb
5
, AshaRostamianfar
6
,
ManjeetK.Bolla
1
, QinWang
1
, JonathanTyrer
7
, EdDicks
7
, AndrewLee
1
, ZhaomingWang
9,10
,
JamieAllen
1
, RenskeKeeman
11
, UrsulaEilber
12
, JulietD.French
5
, XiaoQing Chen
5
,
LauraFachal
7
, KarenMcCue
5
, AmyE.McCart Reed
13
, MayaGhoussaini
7
, JasonS. Carroll
14
,
XiaJiang
4
, HilaryFinucane
4,15
, MarciaAdams
16
, MurielA.Adank
17
, HabibulAhsan
18
,
KristiinaAittomäki
19
, HodaAnton-Culver
20
, NataliaN.Antonenkova
21
, VolkerArndt
22
,
KristanJ.Aronson
23
, BanuArun
24
, PaulL.Auer
25,26
, FrançoisBacot
27
, MyrtoBarrdahl
12
,
CarolineBaynes
7
, MatthiasW.Beckmann
28
, SabineBehrens
12
, JavierBenitez
29,30
,
MarinaBermisheva
31
, LeslieBernstein
32
, CarlBlomqvist
33
, NataliaV.Bogdanova
21,34,35
,
StigE.Bojesen
36,37,38
, BernardoBonanni
39
, Anne-LiseBørresen-Dale
40
, JudithS.Brand
41
,
HiltrudBrauch
42,43,44
, PaulBrennan
45
, HermannBrenner
22,44,46
, LouiseBrinton
47
,
PerBroberg
48
, IanW.Brock
49
, AnnegienBroeks
11
, AngelaBrooks-Wilson
50,51
,
SaraY.Brucker
52
, ThomasBrüning
53
, BarbaraBurwinkel
54,55
, KatjaButterbach
22
,
QiuyinCai
56
, HuiCai
56
, TrinidadCaldés
57
, FedericoCanzian
58
, AngelCarracedo
59,60
,
BrianD.Carter
61
, JoseE.Castelao
62
, TsunL.Chan
63,64
, Ting-YuanDavid Cheng
65
, KeeSeng
Chia
66
, Ji-YeobChoi
67,68
, HansChristiansen
34
, ChristineL.Clarke
69
, NBCSCollaborators†,
MargrietCollée
70
, DonM.Conroy
7
, EmilieCordina-Duverger
71
, StenCornelissen
11
,
DavidG.Cox
72,73
, AngelaCox
49
, SimonS.Cross
74
, JulieM.Cunningham
75
,
KamilaCzene
41
, MaryB.Daly
76
, PeterDevilee
77,78
, KimberlyF.Doheny
16
, ThiloDörk
35
,
Isabeldos-Santos-Silva
79
, MartineDumont
8
, LorraineDurcan
80,81
, MiriamDwek
82
,
DianaM.Eccles
81
, ArifB.Ekici
83
, A.HeatherEliassen
84,85
, CarolinaEllberg
48,86
,
MingajevaElvira
87
, ChristophEngel
88,89
, MikaelEriksson
41
, PeterA.Fasching
28,90
,
JonineFigueroa
47,91
, DieterFlesch-Janys
92,93
, OliviaFletcher
94
, HenrikFlyger
95
,
LinFritschi
96
, ValerieGaborieau
45
, MarikeGabrielson
41
, ManuelaGago-Dominguez
59,97
,
Yu-TangGao
98
, SusanM.Gapstur
61
, JoséA.García-Sáenz
57
, MiaM.Gaudet
61
,
VassiliosGeorgoulias
99
, GrahamG.Giles
100,101
, GordGlendon
102
, MarkS.Goldberg
103,104
,
DavidE.Goldgar
105
, AnnaGonzález-Neira
29
, GretheI.Grenaker Alnæs
40
,
MerviGrip
106
, JacekGronwald
107
, AnneGrundy
108
, PascalGuénel
71
, LotharHaeberle
28
,
EricHahnen
109,110,111
, ChristopherA.Haiman
112
, NiclasHåkansson
113
, UteHamann
114
,
NathalieHamel
27
, SusanHankinson
115
, PatriciaHarrington
7
, StevenN.Hart
116
,
JaanaM.Hartikainen
117,118,119
, MikaelHartman
66,120
, AlexanderHein
28
, JaneHeyworth
121
,
BelyndaHicks
10
, PeterHillemanns
35
, DonaN.Ho
64
, AntoinetteHollestelle
122
,
MaartjeJ.Hooning
122
, RobertN.Hoover
47
, JohnL.Hopper
101
, Ming-FengHou
123
,
Chia-NiHsiung
124
, GuanmengqianHuang
114
, KeithHumphreys
41
, JunkoIshiguro
125,126
,
HidemiIto
125,126
, MotokiIwasaki
127
, HirojiIwata
128
, AnnaJakubowska
107
, WolfgangJanni
129
,
EstherM.John
130,131,132
, NicholaJohnson
94
, KristineJones
10
, MichaelJones
133
,
ArjaJukkola-Vuorinen
134
, RudolfKaaks
12
, MariaKabisch
114
, KatarzynaKaczmarek
107
,
DaeheeKang
67,68,135
, YoshioKasuga
136
, MichaelJ.Kerin
137
, SofiaKhan
138
,
ElzaKhusnutdinova
31,87
, JohannaI.Kiiski
138
, Sung-WonKim
139
, JuliaA.Knight
140,141
,
Veli-MattiKosma
117,118,119
, VesselaN.Kristensen
40,142,143
, UteKrüger
48
, AvaKwong
63,144,145
,
DietherLambrechts
146,147
, LoicLe Marchand
148
, EunjungLee
112
, MinHyuk Lee
149
,
JongWon Lee
150
, ChuenNeng Lee
120,151
, FlavioLejbkowicz
152
, JingmeiLi
41
, JennaLilyquist
116
,
AnnikaLindblom
153
, JolantaLissowska
154
, Wing-YeeLo
42,43
, SibylleLoibl
155
, JirongLong
56
,
ArtitayaLophatananon
156,157
, Jan Lubinski
107
, CraigLuccarini
7
, MichaelP.Lux
28
,
EdmondS.K.Ma
63,64
, RobertJ.MacInnis
100,101
, TomMaishman
80,81
, EnesMakalic
101
,
KathleenE.Malone
158
, IvanaMaleva Kostovska
159
, ArtoMannermaa
117,118,119
,
SiranoushManoukian
160
, JoAnnE.Manson
85,161
, SaraMargolin
162
, ShivaaniMariapun
163
,
MariaElena Martinez
97,164
, KeitaroMatsuo
126,165
, DimitriosMavroudis
99
, JamesMcKay
45
,
CatrionaMcLean
166
, HanneMeijers-Heijboer
17
, AlfonsMeindl
167
, PrimitivaMenéndez
168
,
UshaMenon
169
, JefferyMeyer
75
, HuiMiao
66
, NicolaMiller
137
, NurAishahMohdTaib
170
,
KennethMuir
156,157
, AnnaMarie Mulligan
171,172
, ClaireMulot
173
, SusanL.Neuhausen
32
,
HeliNevanlinna
138
, PatrickNeven
174
, SuneF.Nielsen
36,37
, Dong-YoungNoh
175
,
BørgeG.Nordestgaard
36,37,38
, AaronNorman
116
, OlufunmilayoI.Olopade
176
, JanetE.Olson
116
,
HåkanOlsson
48
, CurtisOlswold
116
, NickOrr
94
, V.ShanePankratz
177
, SueK.Park
67,68,135
,
Tjoung-WonPark-Simon
35
, RachelLloyd
178
, JoseI.A.Perez
179
, PaoloPeterlongo
180
,
JulianPeto
79
, Kelly-AnnePhillips
101,181,182,183
, MilaPinchev
152
, DijanaPlaseska-Karanfilska
159
,
RossPrentice
25
, NadegePresneau
82
, DaryaProkofyeva
87
, ElizabethPugh
16
, KatriPylkäs
184,185
,
BrigitteRack
186
, PaoloRadice
187
, NazneenRahman
188
, GadiRennert
152
, HedyS.Rennert
152
,
ValerieRhenius
7
, AtochaRomero
57,189
, JaneRomm
16
, KathrynJ.Ruddy
190
,
ThomasRüdiger
191
, AnjaRudolph
12
, MatthiasRuebner
28
, EmielJ.T.Rutgers
192
,
EmmanouilSaloustros
193
, DaleP.Sandler
194
, SuleepornSangrajrang
195
, ElinorJ.Sawyer
196
,
DanielF.Schmidt
101
, RitaK.Schmutzler
109,110,111
, AndreasSchneeweiss
54,197
,
MinoukJ.Schoemaker
133
, FredrickSchumacher
198
, PeterSchürmann
35
, RodneyJ.Scott
199,200
,
ChristopherScott
116
, SheilaSeal
188
, CarolineSeynaeve
122
, MitulShah
7
, PriyankaSharma
201
,
Chen-YangShen
202,203
, GraceSheng
112
, MarkE.Sherman
204
, MarthaJ.Shrubsole
56
,
Xiao-OuShu
56
, AnnSmeets
174
, ChristofSohn
197
, MelissaC.Southey
205
, JohnJ.Spinelli
206,207
,
ChristaStegmaier
208
, SarahStewart-Brown
156
, JenniferStone
178,209
, DanielO.Stram
112
,
HaraldSurowy
54,55
, AnthonySwerdlow
133,210
, RullaTamimi
4,84,85
, JackA.Taylor
194,211
,
MariaTengström
117,212,213
, SooH.Teo
163,170
, MaryBeth Terry
214
, DanielC.Tessier
27
,
SomchaiThanasitthichai
215
, KathrinThöne
93
, RobA.E.M.Tollenaar
216
, IanTomlinson
217
,
LingTong
18
, DianaTorres
114,218
, ThérèseTruong
71
, Chiu-ChenTseng
112
, ShoichiroTsugane
219
,
Hans-UlrichUlmer
220
, GiskeUrsin
221,222
, MichaelUntch
223
, CelineVachon
116
,
ChristiJ.vanAsperen
224
, DavidVanDen Berg
112
, AnsM.W.vandenOuweland
70
,
Lizetvander Kolk
225
, RobB.vander Luijt
226
, DanielVincent
27
, JasonVollenweider
75
,
QuintenWaisfisz
17
, ShanWang-Gohrke
227
, ClariceR.Weinberg
228
, CamillaWendt
162
,
AliceS.Whittemore
131,132
, HansWildiers
174
, WalterWillett
85,229
, RobertWinqvist
184,185
,
AlicjaWolk
113
, AnnaH.Wu
112
, LucyXia
112
, TaikiYamaji
127
, XiaohongR.Yang
47
,
ChengHar Yip
230
, Keun-YoungYoo
231,232
, Jyh-CherngYu
233
, WeiZheng
56
, YingZheng
234
,
Bin Zhu
10
, ArgyriosZiogas
20
, EladZiv
235
, ABCTBInvestigators†, kConFab/AOCSInvestigators†,
SunilR.Lakhani
13,236
, AntonisC.Antoniou
1
, ArnaudDroit
8
, IreneL.Andrulis
102,237
,
ChristopherI.Amos
238
, FergusJ.Couch
75
, PaulD.P.Pharoah
1,7
, JennyChang-Claude
12,239
,
PerHall
41,240
, DavidJ.Hunter
4,85
, RogerL.Milne
100,101
, MontserratGarcía-Closas
47
,
MarjankaK.Schmidt
11,241
, StephenJ.Chanock
47
, AlisonM.Dunning
7
, StaceyL.Edwards
5
,
GaryD.Bader
6
, GeorgiaChenevix-Trench
5
, JacquesSimard
8
§, PeterKraft
4,85
§ &
DouglasF.Easton
1,7
§
1
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care,
University of Cambridge, Cambridge, UK.
2
Department of Electron Microscopy/Molecular
Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
3
Department of
Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
4
Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public
Health, Boston, Massachusetts, USA.
5
Department of Genetics and Computational Biology,
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
6
The Donnelly Centre,
University of Toronto, Toronto, Ontario, Canada.
7
Centre for Cancer Genetic Epidemiology,
Department of Oncology, University of Cambridge, Cambridge, UK.
8
Genomics Center, Centre
Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Quebec,
Canada.
9
Department of Computational Biology, St Jude Children’s Research Hospital,
Memphis, Tennessee, USA.
10
Cancer Genomics Research Laboratory (CGR), Division of Cancer
Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
11
Division of
Molecular Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital,
Amsterdam, The Netherlands.
12
Division of Cancer Epidemiology, German Cancer Research
Center (DKFZ), Heidelberg, Germany.
13
UQ Centre for Clinical Research, The University of
Queensland, Brisbane, Australia.
14
Cancer Research UK Cambridge Research Institute,
University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
15
Department of Mathematics,
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
16
Center for Inherited
Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University School of
Medicine, Baltimore, Maryland, USA.
17
Department of Clinical Genetics, VU University Medical
Center, Amsterdam, The Netherlands.
18
Center for Cancer Epidemiology and Prevention,
The University of Chicago, Chicago, Illinois, USA.
19
Department of Clinical Genetics, Helsinki
University Hospital, University of Helsinki, Helsinki, Finland.
20
Department of Epidemiology,
University of California Irvine, Irvine, California, USA.
21
N. N. Alexandrov Research Institute of
Oncology and Medical Radiology, Minsk, Belarus.
22
Division of Clinical Epidemiology and Aging
Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
23
Department of
Public Health Sciences, and Cancer Research Institute, Queen’s University, Kingston, Ontario,
Canada.
24
Department of Breast Medical Oncology, University of Texas MD Anderson Cancer
Center, Houston, Texas, USA.
25
Cancer Prevention Program, Fred Hutchinson Cancer Research
Center, Seattle, Washington, USA.
26
Zilber School of Public Health, University of Wisconsin-
Milwaukee, Milwaukee, Wisconsin, USA.
27
McGill University and Génome Québec Innovation
Centre, Montréal, Quebec, Canada.
28
Department of Gynaecology and Obstetrics, University
Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer
Center Erlangen-EMN, Erlangen, Germany.
29
Human Cancer Genetics Program, Spanish
National Cancer Research Centre, Madrid, Spain.
30
Centro de Investigación en Red de
Enfermedades Raras (CIBERER), Valencia, Spain.
31
Institute of Biochemistry and Genetics,
Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
32
Department of Population
Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.
33
Department of
Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
34
Department of
Radiation Oncology, Hannover Medical School, Hannover, Germany.
35
Gynaecology Research
Unit, Hannover Medical School, Hannover, Germany.
36
Copenhagen General Population Study,
Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
37
Department
of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev,
Denmark.
38
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen,
Denmark.
39
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan,
Italy.
40
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital
Radiumhospitalet, Oslo, Norway.
41
Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet, Stockholm, Sweden.
42
Dr Margarete Fischer-Bosch-Institute of Clinical
Pharmacology, Stuttgart, Germany.
43
University of Tübingen, Tübingen, Germany.
44
German
Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
45
International Agency for Research on Cancer, Lyon, France.
46
Division of Preventive Oncology,
German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT),
Heidelberg, Germany.
47
Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Rockville, Maryland, USA.
48
Department of Cancer Epidemiology, Clinical Sciences,
Lund University, Lund, Sweden.
49
Sheffield Institute for Nucleic Acids (SInFoNiA), Department
of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
50
Genome Sciences Centre,
BC Cancer Agency, Vancouver, British Columbia, Canada.
51
Department of Biomedical
Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
52
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
53
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance,
Institute of the Ruhr University Bochum, Bochum, Germany.
54
Department of Obstetrics and
Gynecology, University of Heidelberg, Heidelberg, Germany.
55
Molecular Epidemiology Group,
C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
56
Division of
Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram
Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
57
Medical
Oncology Department, Hospital Clínico San Carlos, IdISSC (Centro Investigacion Biomedica en
Red), CIBERONC (Instituto de Investigación Sanitaria San Carlos), Madrid, Spain.
58
Genomic
Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
59
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de
Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario
de Santiago, SERGAS, Santiago De Compostela, Spain.
60
Centro de Investigación en Red de
Enfermedades Raras (CIBERER) y Centro Nacional de Genotipado (CEGEN-PRB2), Universidad
de Santiago de Compostela, Santiago De Compostela, Spain.
61
Epidemiology Research
Program, American Cancer Society, Atlanta, Georgia, USA.
62
Oncology and Genetics Unit,
Instituto de Investigacion Biomedica (IBI) Orense-Pontevedra-Vigo, Xerencia de Xestion
Integrada de Vigo-SERGAS, Vigo, Spain.
63
Hong Kong Hereditary Breast Cancer Family Registry,
Happy Valley, Hong Kong.
64
Department of Pathology, Hong Kong Sanatorium and Hospital,
Happy Valley, Hong Kong.
65
Division of Cancer Prevention and Control, Roswell Park Cancer
Institute, Buffalo, New York, USA.
66
Saw Swee Hock School of Public Health, National University
of Singapore, Singapore, Singapore.
67
Department of Biomedical Sciences, Seoul National
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Letter
reSeArCH
University Graduate School, Seoul, South Korea.
68
Cancer Research Institute, Seoul National
University, Seoul, South Korea.
69
Westmead Institute for Medical Research, University of
Sydney, Sydney, Australia.
70
Department of Clinical Genetics, Erasmus University Medical
Center, Rotterdam, The Netherlands.
71
Cancer & Environment Group, Center for Research in
Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University
Paris-Saclay, Villejuif, France.
72
Department of Epidemiology and Biostatistics, School of Public
Health, Imperial College London, London, UK.
73
INSERM U1052, Cancer Research Center of
Lyon, Lyon, France.
74
Academic Unit of Pathology, Department of Neuroscience, University of
Sheffield, Sheffield, UK.
75
Department of Laboratory Medicine and Pathology, Mayo Clinic,
Rochester, Minnesota, USA.
76
Department of Clinical Genetics, Fox Chase Cancer Center,
Philadelphia, Pennsylvania, USA.
77
Department of Pathology, Leiden University Medical Center,
Leiden, The Netherlands.
78
Department of Human Genetics, Leiden University Medical Center,
Leiden, The Netherlands.
79
Department of Non-Communicable Disease Epidemiology, London
School of Hygiene and Tropical Medicine, London, UK.
80
Southampton Clinical Trials Unit,
Faculty of Medicine, University of Southampton, Southampton, UK.
81
Cancer Sciences
Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
82
Department of Biomedical Sciences, Faculty of Science and Technology, University of
Westminster, London, UK.
83
Institute of Human Genetics, University Hospital Erlangen,
Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-
EMN, Erlangen, Germany.
84
Channing Division of Network Medicine, Department of Medicine,
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
85
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston,
Massachusetts, USA.
86
Oncology and Pathology, Department of Clinical Sciences, Lund
University, Lund, Sweden.
87
Department of Genetics and Fundamental Medicine, Bashkir State
University, Ufa, Russia.
88
Institute for Medical Informatics, Statistics and Epidemiology,
University of Leipzig, Leipzig, Germany.
89
LIFE—Leipzig Research Centre for Civilization
Diseases, University of Leipzig, Leipzig, Germany.
90
David Geffen School of Medicine,
Department of Medicine Division of Hematology and Oncology, University of California at Los
Angeles, Los Angeles, California, USA.
91
Usher Institute of Population Health Sciences and
Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
92
Institute for Medical
Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg,
Germany.
93
Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical
Center Hamburg-Eppendorf, Hamburg, Germany.
94
Breast Cancer Now Toby Robins Research
Centre, The Institute of Cancer Research, London, UK.
95
Department of Breast Surgery, Herlev
and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
96
School of Public
Health, Curtin University, Perth, Australia.
97
Moores Cancer Center, University of California San
Diego, La Jolla, California, USA.
98
Department of Epidemiology, Shanghai Cancer Institute,
Shanghai, China.
99
Department of Medical Oncology, University Hospital of Heraklion,
Heraklion, Greece.
100
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria,
Melbourne, Victoria, Australia.
101
Centre for Epidemiology and Biostatistics, Melbourne School
of Population and Global Health, The University of Melbourne, Melbourne, Australia.
102
Fred A.
Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai
Hospital, Toronto, Ontario, Canada.
103
Department of Medicine, McGill University, Montréal,
Quebec, Canada.
104
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University,
Montréal, Quebec, Canada.
105
Department of Dermatology, Huntsman Cancer Institute,
University of Utah School of Medicine, Salt Lake City, Utah, USA.
106
Department of Surgery,
Oulu University Hospital, University of Oulu, Oulu, Finland.
107
Department of Genetics and
Pathology, Pomeranian Medical University, Szczecin, Poland.
108
Centre de Recherche du Centre
Hospitalier de Université de Montréal (CHUM), Université de Montréal, Montréal, Quebec,
Canada.
109
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne,
Cologne, Germany.
110
Center for Integrated Oncology (CIO), University Hospital of Cologne,
Cologne, Germany.
111
Center for Molecular Medicine Cologne (CMMC), University of Cologne,
Cologne, Germany.
112
Department of Preventive Medicine, Keck School of Medicine, University
of Southern California, Los Angeles, California, USA.
113
Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden.
114
Molecular Genetics of Breast Cancer, German
Cancer Research Center (DKFZ), Heidelberg, Germany.
115
Department of Biostatistics &
Epidemiology, University of Massachusetts, Amherst, Amherst, Massachusetts, USA.
116
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
117
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
118
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland,
Kuopio, Finland.
119
Imaging Center, Department of Clinical Pathology, Kuopio University
Hospital, Kuopio, Finland.
120
Department of Surgery, National University Health System,
Singapore, Singapore.
121
School of Population Health, University of Western Australia, Perth,
Australia.
122
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer
Institute, Rotterdam, The Netherlands.
123
Division of Breast Surgery, Department of Surgery,
Kaohsiung Medical University, Kaohsiung, Taiwan.
124
Institute of Biomedical Sciences,
Academia Sinica, Taipei, Taiwan.
125
Division of Epidemiology and Prevention, Aichi Cancer
Center Research Institute, Nagoya, Japan.
126
Department of Epidemiology, Nagoya University
Graduate School of Medicine, Nagoya, Japan.
127
Division of Epidemiology, Center for Public
Health Sciences, National Cancer Center, Tokyo, Japan.
128
Department of Breast Oncology, Aichi
Cancer Center Hospital, Nagoya, Japan.
129
Department of Gynecology and Obstetrics,
University Hospital Ulm, Ulm, Germany.
130
Department of Epidemiology, Cancer Prevention
Institute of California, Fremont, California, USA.
131
Department of Health Research and Policy–
Epidemiology, Stanford University School of Medicine, Stanford, California, USA.
132
Stanford
Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
133
Division
of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
134
Department of
Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.
135
Department of
Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
136
Department of Surgery, Nagano Matsushiro General Hospital, Nagano, Japan.
137
School of
Medicine, National University of Ireland, Galway, Ireland.
138
Department of Obstetrics and
Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
139
Department
of Surgery, Daerim Saint Mary’s Hospital, Seoul, South Korea.
140
Prosserman Centre for Health
Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario,
Canada.
141
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto,
Toronto, Ontario, Canada.
142
Institute of Clinical Medicine, Faculty of Medicine, University of
Oslo, Oslo, Norway.
143
Department of Clinical Molecular Biology, Oslo University Hospital,
University of Oslo, Oslo, Norway.
144
Department of Surgery, The University of Hong Kong, Pok
Fu Lam, Hong Kong.
145
Department of Surgery, Hong Kong Sanatorium and Hospital, Happy
Valley, Hong Kong.
146
Vesalius Research Center, VIB, Leuven, Belgium.
147
Laboratory for
Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
148
University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
149
Department of Surgery,
Soonchunhyang University College of Medicine and Soonchunhyang University Hospital, Seoul,
South Korea.
150
Department of Surgery, University of Ulsan College of Medicine and Asan
Medical Center, Seoul, South Korea.
151
Department of Cardiac, Thoracic and Vascular Surgery,
National University Health System, Singapore, Singapore.
152
Clalit National Cancer Control
Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
153
Department
of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
154
Department of
Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute
of Oncology, Warsaw, Poland.
155
German Breast Group GmbH, Neu Isenburg, Germany.
156
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
157
Institute of Population Health, University of Manchester, Manchester, UK.
158
Division of
Public Health Sciences, Epidemiology Program, Fred Hutchinson Cancer Research Center,
Seattle, Washington, USA.
159
Research Centre for Genetic Engineering and Biotechnology
“Georgi D. Efremov”, Macedonian Academy of Sciences and Arts, Skopje, Republic of
Macedonia.
160
Unit of Medical Genetics, Department of Preventive and Predictive Medicine,
Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei
Tumori (INT), Milan, Italy.
161
Department of Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts, USA.
162
Department of Oncology–Pathology, Karolinska
Institutet, Stockholm, Sweden.
163
Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
164
Department of Family Medicine and Public Health, University of California San Diego,
La Jolla, California, USA.
165
Division of Molecular Medicine, Aichi Cancer Center Research
Institute, Nagoya, Japan.
166
Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
167
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
168
Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
169
Gynaecological
Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health,
University College London, London, UK.
170
Breast Cancer Research Unit, Cancer Research
Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
171
Department of
Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
172
Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
173
Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris, France.
174
Leuven
Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University
Hospitals Leuven, Leuven, Belgium.
175
Department of Surgery, Seoul National University
College of Medicine, Seoul, South Korea.
176
Center for Clinical Cancer Genetics and Global
Health, The University of Chicago, Chicago, Illinois, USA.
177
University of New Mexico Health
Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA.
178
The Curtin UWA
Centre for Genetic Origins of Health and Disease, Curtin University and University of Western
Australia, Perth, Australia.
179
Servicio de Cirugía General y Especialidades, Hospital Monte
Naranco, Oviedo, Spain.
180
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of
Molecular Oncology, Milan, Italy.
181
Peter MacCallum Cancer Center, Melbourne, Australia.
182
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne,
Australia.
183
Department of Medicine, St Vincent’s Hospital, The University of Melbourne,
Fitzroy, Australia.
184
Laboratory of Cancer Genetics and Tumor Biology, Cancer and
Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
185
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu,
Oulu, Finland.
186
Department of Gynecology and Obstetrics, Ludwig-Maximilians University of
Munich, Munich, Germany.
187
Unit of Molecular Bases of Genetic Risk and Genetic Testing,
Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e
Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
188
Section of
Cancer Genetics, The Institute of Cancer Research, London, UK.
189
Medical Oncology
Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
190
Department of
Oncology, Mayo Clinic, Rochester, Minnesota, USA.
191
Institute of Pathology, Staedtisches
Klinikum Karlsruhe, Karlsruhe, Germany.
192
Department of Surgery, The Netherlands Cancer
Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
193
Hereditary
Cancer Clinic, University Hospital of Heraklion, Heraklion, Greece.
194
Epidemiology Branch,
National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North
Carolina, USA.
195
National Cancer Institute, Bangkok, Thailand.
196
Research Oncology, Guy’s
Hospital, King’s College London, London, UK.
197
National Center for Tumor Diseases, University
of Heidelberg, Heidelberg, Germany.
198
Department of Epidemiology and Biostatistics, Case
Western Reserve University, Cleveland, Ohio, USA.
199
Division of Molecular Medicine, Pathology
North, John Hunter Hospital, Newcastle, Australia.
200
Discipline of Medical Genetics, School of
Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan,
Australia.
201
Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas,
USA.
202
School of Public Health, China Medical University, Taichung, Taiwan.
203
Taiwan Biobank,
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
204
Division of Cancer
Prevention, National Cancer Institute, Rockville, Maryland, USA.
205
Genetic Epidemiology
Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
206
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
207
School of Population and Public Health, University of British Columbia, Vancouver, British
Columbia, Canada.
208
Saarland Cancer Registry, Saarbrücken, Germany.
209
Department of
Obstetrics and Gynaecology, University of Melbourne and the Royal Women’s Hospital,
Melbourne, Australia.
210
Division of Breast Cancer Research, The Institute of Cancer Research,
London, UK.
211
Epigenetic and Stem Cell Biology Laboratory, National Institute of
Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
212
Cancer
Center, Kuopio University Hospital, Kuopio, Finland.
213
Institute of Clinical Medicine, Oncology,
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