Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
Kuchenbaecker, Karoline B.
Hopper, John L.
Milne, Roger L.
Bolla, Manjeet K.
Andrulis, Irene L.
Antonenkova, Natalia N.
Arun, Banu K.
Blot, William J.
Bogdanova, Natalia V.
Bojesen, Stig E.
Brand, Judith S.
Buys, Saundra S.
Claes, Kathleen B.M.
Cross, Simon S.
Daly, Mary B.
de la Hoya, Miguel
De Leeneer, Kim
Domchek, Susan M.
Fasching, Peter A.
GEMO Study Collaborators
Giles, Graham G.
Godwin, Andrew K.
Goldgar, David E.
Greene, Mark H.
Haiman, Christopher A.
Hansen, Thomas V. O.
Hartikainen, Jaana M.
Hogervorst, Frans B.L.
Hendricks, Carolyn B.
Hulick, Peter J.
Hunter, David J.
Imyanitov, Evgeny N.
Jensen, Uffe Birk
John, Esther M.
Beauparlant, Charles Joly
Karlan, Beth Y.
Kerin, Michael J.
Knight, Julia A.
Le Marchand, Loic
Lee, Chuen Neng
Lee, Min Hyuk
Mai, Phuong L.
Mulligan, Anna Marie
Nathanson, Katherine L.
Newcomb, Polly A.
Nussbaum, Robert L.
Olopade, Olufunmilayo I.
Phelan, Catherine M.
Ramus, Susan J.
Rashid, Muhammad Usman
Sawyer, Elinor J.
Schmidt, Marjanka K.
Schmutzler, Rita K.
Schoemaker, Minouk J.
Shrubsole, Martha J.
Szabo, Csilla I.
Teixeira, Manuel R.
Teo, Soo H.
Terry, Mary Beth
Tessier, Daniel C.
Toland, Amanda E.
Van den Ouweland, Ans M.W.
Ven den Berg, David
Weitze, Jeffrey N.
Whittemore, Alice S.
Wu, Anna H.
Pharoah, Paul D.P.
Dunning, Alison M.
Couch, Fergus J.
Antoniou, Antonis C.
Easton, Douglas F.
Dorfling, Cecilia Maria
Van Rensburg, Elizabeth J.
Genetic risk factor
BRAC1 mutation carriers
Genome-wide association studies (GWAS)
Single nucleotide polymorphism (SNP)
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AbstractBACKGROUND : Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide
polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
METHOD : We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than
1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624
controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association
Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium
of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify
independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer
Genome Atlas (TCGA) were used for functional annotation.
RESULTS : Analysis of data from European descendants found evidence for four independent association signals at
12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9),
rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4)
identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC
ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated
with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African
descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin
interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the
strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression
of PTHLH and its nearby gene CCDC91 at P < 0.05.
CONCLUSION : This study identified four independent association signals at 12p11 and revealed potentially functional
variants, providing additional insights into the underlying biological mechanism(s) for the association observed
between variants at 12p11 and breast cancer risk.
Additional file 1: Table S1. Ethical committees that approved each
Additional file 2: Table S3. Independent association signals for risk
of estrogen (ER)-positive and ER-negative breast cancer in European
Additional file 3: Table S4. Associations of independent signals for
breast cancer risk for BRCA1 mutation carriers.
Additional file 4: Table S5. Associations of independent signals for breast
cancer risk in women of East Asian and African descent.
Additional file 5: Table S2. List of the variants that were retained for
further functional annotation in European descendants.
Additional file 6: Table S6. Putative functional SNPs identified using
the ENCODE data.
Additional file 7: Table S7. Gene expression analysis for putative
functional SNPs using 1,006 breast tumor samples in TCGA.
Zeng et al. 2016, 'Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus', Breast Cancer Research, vol. 18, art. #64, pp. 1-21.
Copyright/License© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locusDorfling, Cecilia Maria; van Rensburg, Elizabeth J.; Zeng, Chenjie; Guo, Xingyi; Long, Jirong; Kuchenbaecker, Karoline B.; Droit, Arnaud; Michailidou, Kyriaki; Ghoussaini, Maya; Kar, Siddhartha; et al. (BioMed Central, 2016-08-23)Additional file 1: Table S1. Ethical committees that approved each
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