Abstract
Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26–1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20–1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28–1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14–1.68), 1.48 (1.25–1.74), and 1.58 (1.28–1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12–1.43) at rs1219648, 1.22 (1.07–1.38) at rs2981582, 1.21 (1.07–1.36) at rs2981579, and 1.18 (1.04–1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00–1.34), 1.15 (1.02–1.29), and 1.15 (1.01–1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.
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Abbreviations
- CI:
-
Confidence interval
- ER:
-
Estrogen receptor
- GWAS:
-
Genome-wide association studies
- HWE:
-
Hardy–Weinberg equilibrium
- LD:
-
Linkage disequilibrium
- MAF:
-
Minor allele frequency
- OR:
-
Odds ratio
- PR:
-
Progesterone receptor
- SNP:
-
Single nucleotide polymorphisms
References
Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J, Friedman E, Narod S, Olshen AB, Gregersen P et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci USA 105:4340–4345
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874
Milne RL, Ribas G, Gonzalez-Neira A, Fagerholm R, Salas A, Gonzalez E, Dopazo J, Nevanlinna H, Robledo M, Benitez J (2006) ERCC4 associated with breast cancer risk: a two-stage case–control study using high-throughput genotyping. Cancer Res 66:9420–9427
Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352–358
Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093
Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, Jakobsdottir M, Bergthorsson JT, Gudmundsson J, Aben KK et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706
Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, Masson G, Jakobsdottir M, Thorlacius S, Helgason A et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869
Dai J, Hu Z, Jiang Y, Shen H, Dong J, Ma H (2012) Breast cancer risk assessment with five independent genetic variants and two risk factors in Chinese women. Breast Cancer Res 14:R17
Harlid S, Ivarsson MI, Butt S, Grzybowska E, Eyfjord JE, Lenner P, Forsti A, Hemminki K, Manjer J, Dillner J et al (2012) Combined effect of low-penetrant SNPs on breast cancer risk. Br J Cancer 106:389–396
Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803
McCracken M, Olsen M, Chen MS Jr, Jemal A, Thun M, Cokkinides V, Deapen D, Ward E (2007) Cancer incidence, mortality, and associated risk factors among Asian Americans of Chinese, Filipino, Vietnamese, Korean, and Japanese ethnicities. CA Cancer J Clin 57:190–205
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Sueta A, Ito H, Kawase T, Hirose K, Hosono S, Yatabe Y, Tajima K, Tanaka H, Iwata H, Iwase H et al (2012) A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Treat 132:711–721
Long J, Shu XO, Cai Q, Gao YT, Zheng Y, Li G, Li C, Gu K, Wen W, Xiang YB et al (2010) Evaluation of breast cancer susceptibility loci in Chinese women. Cancer Epidemiol Biomarkers Prev 19:2357–2365
Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41:324–328
Chan M, Chan MW, Loh TW, Law HY, Yoon CS, Than SS, Chua JM, Wong CY, Yong WS, Yap YS et al (2011) Evaluation of nanofluidics technology for high-throughput SNP genotyping in a clinical setting. J Mol Diagn 13:305–312
Raskin L, Pinchev M, Arad C, Lejbkowicz F, Tamir A, Rennert HS, Rennert G, Gruber SB (2008) FGFR2 is a breast cancer susceptibility gene in Jewish and Arab Israeli populations. Cancer Epidemiol Biomarkers Prev 17:1060–1065
Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41:579–584
The_International_HapMap_Consortium (2003) The International HapMap project. Nature 426:789–796
Abraham JE, Maranian MJ, Spiteri I, Russell R, Ingle S, Luccarini C, Earl HM, Pharoah PD, Dunning AM, Caldas C (2012) Saliva samples are a viable alternative to blood samples as a source of DNA for high throughput genotyping. BMC Med Genomics 5:19
Gonzalez JR, Armengol L, Sole X, Guino E, Mercader JM, Estivill X, Moreno V (2007) SNPassoc: an R package to perform whole genome association studies. Bioinformatics 23:644–645
Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 76:887–893
Zheng W, Wen W, Gao YT, Shyr Y, Zheng Y, Long J, Li G, Li C, Gu K, Cai Q et al (2010) Genetic and clinical predictors for breast cancer risk assessment and stratification among Chinese women. J Natl Cancer Inst 102:972–981
Sueta A, Ito H, Kawase T, Hirose K, Hosono S, Yatabe Y, Tajima K, Tanaka H, Iwata H, Iwase H et al (2012) A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Treat 132:711–721
Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42:504–507
Cai Q, Wen W, Qu S, Li G, Egan KM, Chen K, Deming SL, Shen H, Shen CY, Gammon MD et al (2011) 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 71:1344–1355
Han W, Woo JH, Yu JH, Lee MJ, Moon HG, Kang D, Noh DY (2011) Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomarkers Prev 20:793–798
Tian C, Kosoy R, Lee A, Ransom M, Belmont JW, Gregersen PK, Seldin MF (2008) Analysis of East Asia genetic substructure using genome-wide SNP arrays. PLoS One 3:e3862
Fu F, Wang C, Huang M, Song C, Lin S, Huang H (2012) Polymorphisms in second intron of the FGFR2 gene are associated with the risk of early-onset breast cancer in Chinese Han women. Tohoku J Exp Med 226:221–229
Udler MS, Meyer KB, Pooley KA, Karlins E, Struewing JP, Zhang J, Doody DR, MacArthur S, Tyrer J, Pharoah PD et al (2009) FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. Hum Mol Genet 18:1692–1703
Barnholtz-Sloan JS, Shetty PB, Guan X, Nyante SJ, Luo J, Brennan DJ, Millikan RC (2010) FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women. Carcinogenesis 31:1417–1423
Meyer KB, Maia AT, O’Reilly M, Teschendorff AE, Chin SF, Caldas C, Ponder BA (2008) Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6:e108
Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G, Helgason A, Jonasdottir A, Besenbacher S, Kostic JP, Fackenthal JD et al (2010) Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus. PLoS Genet 6:e1001029
Skol AD, Scott LJ, Abecasis GR, Boehnke M (2006) Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 38:209–213
Acknowledgments
This work was supported by a grant from the National Medical Research Council of Singapore (NMRC/1194/2008). We are also grateful to the staff of Singapore Institute for Clinical Sciences for the use of their BioMark equipment, and the SingHealth Tissue Repository for providing blood samples.
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The authors declare no conflict of interest.
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The authors declare that the experiments comply with the current laws of Singapore in which they were performed.
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Chan, M., Ji, S.M., Liaw, C.S. et al. Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population. Breast Cancer Res Treat 136, 209–220 (2012). https://doi.org/10.1007/s10549-012-2234-y
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DOI: https://doi.org/10.1007/s10549-012-2234-y