The University of Southampton
University of Southampton Institutional Repository

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
0143-3334
1012-1019
Purrington, K.S.
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Slager, S.
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Eccles, D.
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Yannoukakos, D.
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Fasching, P.A.
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Miron, P.
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Carpenter, J.
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Chang-Claude, J.
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Martin, N.G.
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Montgomery, G.W.
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Fostira, F.
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Kotoula, V.
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Lakis, S.
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Dimopoulos, M.A.
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Skarlos, D.
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Pectasides, D.
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Fountzilas, G.
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Scholz, C.
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Neugebauer, J.
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Clarke, C.
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Flesch-Janys, D.
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Olson, J.E.
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Ingle, J.N.
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Olswold, C.
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Slettedahl, S.
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Anderson, S.K.
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Visscher, D.W.
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Cafourek, V.L.
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Sicotte, H.
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Prodduturi, N.
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Weiderpass, E.
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Bernstein, L.
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Ziogas, A.
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Ivanovich, J.
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Giles, G.G.
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Baglietto, L.
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Southey, M.
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Kosma, V.-M.
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Fischer, H.-P.
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Reed, M.W.R.
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Cross, S.S.
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Deming-Halverson, S.
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Shrubsole, M.
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Cai, Q.
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Shu, X.-O.
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Daly, M.
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Weaver, J.
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Ross, E.
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Klemp, J.
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Sharma, P.
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Torres, D.
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Rudiger, T.
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Wolfing, H.
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Ulmer, H.-U.
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Khoury, T.
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Kumar, S.
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Shapiro, C.L.
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Greco, D.
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Heikkila, P.
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Aittomaki, K.
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Blomqvist, C.
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Irwanto, A.
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Liu, J.
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Pankratz, V.S.
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Wang, X.
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Severi, G.
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Mannermaa, A.
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Brauch, H.
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Cox, A.
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Zheng, W.
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Godwin, A.K.
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Couch, F.J.
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Purrington, K.S.
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Slager, S.
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Eccles, D.
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Yannoukakos, D.
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Miron, P.
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Chang-Claude, J.
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Martin, N.G.
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Kristensen, V.
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Gerty, S.M.
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Durcan, L.
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Konstantopoulou, I.
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Fostira, F.
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Lakis, S.
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Dimopoulos, M.A.
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Skarlos, D.
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Pectasides, D.
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Fountzilas, G.
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Ruebner, M.
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Giles, G.G.
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Deming-Halverson, S.
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Ross, E.
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Rudiger, T.
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Wolfing, H.
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Khoury, T.
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Greco, D.
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Heikkila, P.
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Aittomaki, K.
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Blomqvist, C.
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Irwanto, A.
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Liu, J.
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Pankratz, V.S.
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Wang, X.
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Severi, G.
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Mannermaa, A.
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Hall, P.
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Brauch, H.
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Cox, A.
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Zheng, W.
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Godwin, A.K.
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Hamann, U.
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Toland, A.E.
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Nevanlinna, H.
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Vachon, C.M.
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Couch, F.J.
cf80080b-6123-4085-99cd-e682f0823efe

Purrington, K.S., Slager, S. and Eccles, D. et al. (2014) Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. Carcinogenesis, 35 (5), 1012-1019. (doi:10.1093/carcin/bgt404). (PMID:24325915)

Record type: Article

Abstract

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

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Accepted/In Press date: 27 November 2013
e-pub ahead of print date: 9 December 2013
Published date: May 2014
Organisations: Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, Cancer Sciences, Clinical Trials Unit

Identifiers

Local EPrints ID: 382482
URI: http://eprints.soton.ac.uk/id/eprint/382482
ISSN: 0143-3334
PURE UUID: 1896e06b-5d27-441a-9454-156b2cddbe07
ORCID for D. Eccles: ORCID iD orcid.org/0000-0002-9935-3169
ORCID for W.J. Tapper: ORCID iD orcid.org/0000-0002-5896-1889

Catalogue record

Date deposited: 06 Oct 2015 09:31
Last modified: 15 Mar 2024 03:02

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Contributors

Author: K.S. Purrington
Author: S. Slager
Author: D. Eccles ORCID iD
Author: D. Yannoukakos
Author: P.A. Fasching
Author: P. Miron
Author: J. Carpenter
Author: J. Chang-Claude
Author: N.G. Martin
Author: G.W. Montgomery
Author: V. Kristensen
Author: H. Anton-Culver
Author: P. Goodfellow
Author: W.J. Tapper ORCID iD
Author: S. Rafiq
Author: S.M. Gerty
Author: L. Durcan
Author: I. Konstantopoulou
Author: F. Fostira
Author: A. Vratimos
Author: P. Apostolou
Author: I. Konstanta
Author: V. Kotoula
Author: S. Lakis
Author: M.A. Dimopoulos
Author: D. Skarlos
Author: D. Pectasides
Author: G. Fountzilas
Author: M.W. Beckmann
Author: A. Hein
Author: M. Ruebner
Author: A.B. Ekici
Author: A. Hartmann
Author: R. Schulz-Wendtland
Author: S.P. Renner
Author: W. Janni
Author: B. Rack
Author: C. Scholz
Author: J. Neugebauer
Author: U. Andergassen
Author: M.P. Lux
Author: L. Haeberle
Author: C. Clarke
Author: N. Pathmanathan
Author: A. Rudolph
Author: D. Flesch-Janys
Author: S. Nickels
Author: J.E. Olson
Author: J.N. Ingle
Author: C. Olswold
Author: S. Slettedahl
Author: J.E. Eckel-Passow
Author: S.K. Anderson
Author: D.W. Visscher
Author: V.L. Cafourek
Author: H. Sicotte
Author: N. Prodduturi
Author: E. Weiderpass
Author: L. Bernstein
Author: A. Ziogas
Author: J. Ivanovich
Author: G.G. Giles
Author: L. Baglietto
Author: M. Southey
Author: V.-M. Kosma
Author: H.-P. Fischer
Author: M.W.R. Reed
Author: S.S. Cross
Author: S. Deming-Halverson
Author: M. Shrubsole
Author: Q. Cai
Author: X.-O. Shu
Author: M. Daly
Author: J. Weaver
Author: E. Ross
Author: J. Klemp
Author: P. Sharma
Author: D. Torres
Author: T. Rudiger
Author: H. Wolfing
Author: H.-U. Ulmer
Author: A. Forsti
Author: T. Khoury
Author: S. Kumar
Author: R. Pilarski
Author: C.L. Shapiro
Author: D. Greco
Author: P. Heikkila
Author: K. Aittomaki
Author: C. Blomqvist
Author: A. Irwanto
Author: J. Liu
Author: V.S. Pankratz
Author: X. Wang
Author: G. Severi
Author: A. Mannermaa
Author: D. Easton
Author: P. Hall
Author: H. Brauch
Author: A. Cox
Author: W. Zheng
Author: A.K. Godwin
Author: U. Hamann
Author: C. Ambrosone
Author: A.E. Toland
Author: H. Nevanlinna
Author: C.M. Vachon
Author: F.J. Couch

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