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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Identification of novel common breast cancer risk variants at the 6q25 locus among Latinas

Authors: Joshua Hoffman, Laura Fejerman, Donglei Hu, Scott Huntsman, Min Li, Esther M. John, Gabriela Torres-Mejia, Larry Kushi, Yuan Chun Ding, Jeffrey Weitzel, Susan L. Neuhausen, Paul Lott, Magdalena Echeverry, Luis Carvajal-Carmona, Esteban Burchard, Celeste Eng, Jirong Long, Wei Zheng, Olufunmilayo Olopade, Dezheng Huo, Christopher Haiman, Elad Ziv, COLUMBUS Consortium

Published in: Breast Cancer Research | Issue 1/2019

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Abstract

Background

Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.

Methods

We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.

Results

We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10− 8 - 6.0 × 10− 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70–0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78–0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91–0.97; p = 0.0017).

Conclusion

Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.
Appendix
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Literature
1.
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684–9.CrossRef
2.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.CrossRef
3.
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789–92.CrossRef
4.
Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007;11(2):103–5.CrossRef
5.
Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087–93.CrossRef
6.
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39(7):870–4.CrossRef
7.
Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, Masson G, Jakobsdottir M, Thorlacius S, Helgason A, et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet. 2007;39(7):865–9.CrossRef
8.
Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet. 2009;41(5):585–90.CrossRef
9.
Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet. 2009;41(5):579–84.CrossRef
10.
Long J, Cai Q, Shu XO, Qu S, Li C, Zheng Y, Gu K, Wang W, Xiang YB, Cheng J, et al. Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium. PLoS Genet. 2010;6(6):e1001002.CrossRef
11.
Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS, et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet. 2010;42(6):504–7.CrossRef
12.
Wang X, Pankratz VS, Fredericksen Z, Tarrell R, Karaus M, McGuffog L, Pharaoh PD, Ponder BA, Dunning AM, Peock S, et al. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2010;19(14):2886–97.CrossRef
13.
Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L, Healey S, Lee A, Peterlongo P, Manoukian S, Peissel B, et al. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2011;20(16):3304–21.CrossRef
14.
Cai Q, Long J, Lu W, Qu S, Wen W, Kang D, Lee JY, Chen K, Shen H, Shen CY, et al. Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. Hum Mol Genet. 2011;20(24):4991–9.CrossRef
15.
Haiman CA, Chen GK, Vachon CM, Canzian F, Dunning A, Millikan RC, Wang X, Ademuyiwa F, Ahmed S, Ambrosone CB, et al. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nat Genet. 2011;43(12):1210–4.CrossRef
16.
Couch FJ, Gaudet MM, Antoniou AC, Ramus SJ, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, Wang X, Kirchhoff T, et al. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomark Prev. 2012;21(4):645–57.CrossRef
17.
Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, Dennis J, Wang Q, Humphreys MK, Luccarini C, et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. 2012;44(3):312–8.CrossRef
18.
Siddiq A, Couch FJ, Chen GK, Lindstrom S, Eccles D, Millikan RC, Michailidou K, Stram DO, Beckmann L, Rhie SK, et al. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet. 2012;21(24):5373–84.CrossRef
19.
Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK, Chang-Claude J, Bojesen SE, Bolla MK, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353–61 361e351-352.CrossRef
20.
Zheng W, Zhang B, Cai Q, Sung H, Michailidou K, Shi J, Choi JY, Long J, Dennis J, Humphreys MK, et al. Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls. Hum Mol Genet. 2013;22(12):2539–50.CrossRef
21.
Huo D, Feng Y, Haddad S, Zheng Y, Yao S, Han YJ, Ogundiran TO, Adebamowo C, Ojengbede O, Falusi AG, et al. Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer. Hum Mol Genet. 2016;25(21):4835–46.PubMedPubMedCentral
22.
Fejerman L, Chen GK, Eng C, Huntsman S, Hu D, Williams A, Pasaniuc B, John EM, Via M, Gignoux C, et al. Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas. Hum Mol Genet. 2012;21(8):1907–17.CrossRef
23.
Fejerman L, Ahmadiyeh N, Hu D, Huntsman S, Beckman KB, Caswell JL, Tsung K, John EM, Torres-Mejia G, Carvajal-Carmona L, et al. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat Commun. 2014;5:5260.CrossRef
24.
Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL, et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet. 2009;41(3):324–8.CrossRef
25.
Cai Q, Wen W, Qu S, Li G, Egan KM, Chen K, Deming SL, Shen H, Shen CY, Gammon MD, et al. Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of chinese, Japanese, and European ancestry. Cancer Res. 2011;71(4):1344–55.CrossRef
26.
Hein R, Maranian M, Hopper JL, Kapuscinski MK, Southey MC, Park DJ, Schmidt MK, Broeks A, Hogervorst FB, Bueno-de-Mesquita HB, et al. Comparison of 6q25 breast cancer hits from Asian and European genome wide association studies in the Breast Cancer Association Consortium (BCAC). PLoS One. 2012;7(8):e42380.CrossRef
27.
Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, Healey CS, Kar S, Pooley KA, Lopez-Knowles E, et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat Genet. 2016;48(4):374–86.CrossRef
28.
Brand JS, Li J, Humphreys K, Karlsson R, Eriksson M, Ivansson E, Hall P, Czene K. Identification of two novel mammographic density loci at 6Q25.1. Breast Cancer Res. 2015;17:75.CrossRef
29.
Ellingjord-Dale M, Grotmol T, Lee E, Van Den Berg DJ, Hofvind S, Couto E, Sovio U, Dos-Santos-Silva I, Ursin G. Breast cancer susceptibility variants and mammographic density phenotypes in norwegian postmenopausal women. Cancer Epidemiol Biomark Prev. 2014;23(9):1752–63.CrossRef
30.
Mariapun S, Ho WK, Kang PC, Li J, Lindstrom S, Yip CH, Teo SH. Variants in 6q25.1 are associated with mammographic density in Malaysian Chinese women. Cancer Epidemiol Biomark Prev. 2016;25(2):327–33.CrossRef
31.
Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, Wen W, Delahanty RJ, Lu W, Gao YT, et al. Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer. PLoS Genet. 2012;8(2):e1002532.CrossRef
32.
Gonzalez Burchard E, Borrell LN, Choudhry S, Naqvi M, Tsai HJ, Rodriguez-Santana JR, Chapela R, Rogers SD, Mei R, Rodriguez-Cintron W, et al. Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research. Am J Public Health. 2005;95(12):2161–8.CrossRef
33.
Park SL, Cheng I, Haiman CA. Genome-wide association studies of cancer in diverse populations. Cancer Epidemiol Biomarkers Prev. 2018; 27(4):405–17.
34.
Lisker R, Ramirez E, Briceno RP, Granados J, Babinsky V. Gene frequencies and admixture estimates in four Mexican urban centers. Hum Biol. 1990;62(6):791–801.PubMed
35.
Hanis CL, Hewett-Emmett D, Bertin TK, Schull WJ. Origins of U.S. Hispanics. Implications for diabetes. Diabetes Care. 1991;14(7):618–27.CrossRef
36.
Williams RC, Knowler WC, Pettitt DJ, Long JC, Rokala DA, Polesky HF, Hackenberg RA, Steinberg AG, Bennett PH. The magnitude and origin of European-American admixture in the Gila River Indian Community of Arizona: a union of genetics and demography. Am J Hum Genet. 1992;51(1):101–10.PubMedPubMedCentral
37.
Bertoni B, Budowle B, Sans M, Barton SA, Chakraborty R. Admixture in Hispanics: distribution of ancestral population contributions in the Continental United States. Hum Biol. 2003;75(1):1–11.CrossRef
38.
MacDonald DJ, Blazer KR, Weitzel JN. Extending comprehensive cancer center expertise in clinical cancer genetics and genomics to diverse communities: the power of partnership. J Natl Compr Canc Netw. 2010;8(5):615–24.CrossRef
39.
Feng Y, Stram DO, Rhie SK, Millikan RC, Ambrosone CB, John EM, Bernstein L, Zheng W, Olshan AF, Hu JJ, et al. A comprehensive examination of breast cancer risk loci in African American women. Hum Mol Genet. 2014;23(20):5518–26.CrossRef
40.
Michailidou K, Lindstrom S, Dennis J, Beesley J, Hui S, Kar S, Lemacon A, Soucy P, Glubb D, Rostamianfar A, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551(7678):92–4.CrossRef
41.
Fejerman L, Romieu I, John EM, Lazcano-Ponce E, Huntsman S, Beckman KB, Perez-Stable EJ, Gonzalez Burchard E, Ziv E, Torres-Mejia G. European ancestry is positively associated with breast cancer risk in Mexican women. Cancer Epidemiol Biomark Prev. 2010;19(4):1074–82.CrossRef
42.
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8.CrossRef
43.
Genomes Project C, Abecasis GR, Auton A, Brooks LD, MA DP, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65.CrossRef
44.
Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.CrossRef
45.
Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5(6):e1000529.CrossRef
46.
Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26(22):2867–73.CrossRef
47.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904–9.CrossRef
48.
Alexander DH, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. 2009;19(9):1655–64.CrossRef
49.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.CrossRef
50.
Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26(17):2190–1.CrossRef
51.
Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790–7.CrossRef
52.
Long J, Zhang B, Signorello LB, Cai Q, Deming-Halverson S, Shrubsole MJ, Sanderson M, Dennis J, Michailidou K, Easton DF, et al. Evaluating genome-wide association study-identified breast cancer risk variants in African-American women. PLoS One. 2013;8(4):e58350.CrossRef
53.
Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G, Helgason A, Jonasdottir A, Besenbacher S, Kostic JP, Fackenthal JD, et al. Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus. PLoS Genet. 2010;6(7):e1001029.CrossRef
54.
Cummings SR, Lee JS, Lui LY, Stone K, Ljung BM, Cauleys JA. Sex hormones, risk factors, and risk of estrogen receptor-positive breast cancer in older women: a long-term prospective study. Cancer Epidemiol Biomark Prev. 2005;14(5):1047–51.CrossRef
55.
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281(23):2189–97.CrossRef
56.
Ziv E, Tice J, Smith-Bindman R, Shepherd J, Cummings S, Kerlikowske K. Mammographic density and estrogen receptor status of breast cancer. Cancer Epidemiol Biomark Prev. 2004;13(12):2090–5.
57.
Jiang P, Li Y, Poleshko A, Medvedeva V, Baulina N, Zhang Y, Zhou Y, Slater CM, Pellegrin T, Wasserman J, et al. The protein encoded by the CCDC170 breast cancer gene functions to organize the golgi-microtubule network. EBioMedicine. 2017;22:28–43.CrossRef
58.
Yamamoto-Ibusuki M, Yamamoto Y, Fujiwara S, Sueta A, Yamamoto S, Hayashi M, Tomiguchi M, Takeshita T, Iwase H. C6ORF97-ESR1 breast cancer susceptibility locus: influence on progression and survival in breast cancer patients. Eur J Hum Genet. 2015;23(7):949–56.CrossRef
59.
Dunbier AK, Anderson H, Ghazoui Z, Lopez-Knowles E, Pancholi S, Ribas R, Drury S, Sidhu K, Leary A, Martin LA, et al. ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1. PLoS Genet. 2011;7(4):e1001382.CrossRef
60.
Perry JJ, Ballard GD, Albert AE, Dobrolecki LE, Malkas LH, Hoelz DJ. Human C6orf211 encodes Armt1, a protein carboxyl methyltransferase that targets PCNA and is linked to the DNA damage response. Cell Rep. 2015;10(8):1288–96.CrossRef
61.
Veeraraghavan J, Tan Y, Cao XX, Kim JA, Wang X, Chamness GC, Maiti SN, Cooper LJ, Edwards DP, Contreras A, et al. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun. 2014;5:4577.CrossRef
62.
Xiao R, Boehnke M. Quantifying and correcting for the winner's curse in genetic association studies. Genet Epidemiol. 2009;33(5):453–62.CrossRef
Metadata
Title
Identification of novel common breast cancer risk variants at the 6q25 locus among Latinas
Authors
Joshua Hoffman
Laura Fejerman
Donglei Hu
Scott Huntsman
Min Li
Esther M. John
Gabriela Torres-Mejia
Larry Kushi
Yuan Chun Ding
Jeffrey Weitzel
Susan L. Neuhausen
Paul Lott
Magdalena Echeverry
Luis Carvajal-Carmona
Esteban Burchard
Celeste Eng
Jirong Long
Wei Zheng
Olufunmilayo Olopade
Dezheng Huo
Christopher Haiman
Elad Ziv
COLUMBUS Consortium
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-1085-9

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