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Breast Cancer Research and Treatment

, Volume 163, Issue 1, pp 131–138 | Cite as

A polygenic risk score for breast cancer risk in a Taiwanese population

  • Yi-Chen Hsieh
  • Shih-Hsin Tu
  • Chien-Tien Su
  • Er-Chieh Cho
  • Chih-Hsiung Wu
  • Mao-Chih Hsieh
  • Shiyng-Yu Lin
  • Yun-Ru Liu
  • Chin-Sheng HungEmail author
  • Hung-Yi ChiouEmail author
Epidemiology

Abstract

Background

Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population.

Methods

In total, 446 breast cancer patients and 514 healthy controls were recruited for this case–control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC).

Results

Logistic regression results showed that nine individual SNPs were significantly associated with breast cancer risk after multiple testing. Among all SNPs, six variants, namely FGFR2 (rs2981582), HCN1 (rs981782), MAP3K1 (rs889312), TOX3 (rs3803662), ZNF365 (rs10822013), and RAD51B (rs3784099), were selected to create PRS model. A dose–response association was observed between breast cancer risk and the PRS. Women in the highest quartile of PRS had a significantly increased risk compared to women in the lowest quartile (odds ratio 2.26; 95% confidence interval 1.51–3.38). The AUC for a model which contained the PRS in addition to clinical risk factors was 66.52%, whereas that for a model which with established risk factors only was 63.38%.

Conclusions

Our data identified a genetic risk predictor of breast cancer in Taiwanese population and suggest that risk models including PRS and clinical risk factors are useful in discriminating women at high risk of breast cancer from those at low risk.

Keywords

Breast cancer Polygenic risk score Common variants Risk prediction 

Notes

Acknowledgements

This study was supported by the Health and Welfare Surcharge of Tobacco Products, Ministry of Health and Welfare to the Comprehensive Cancer Center of Taipei Medical University (MOHW105-TDU-B-212-134001), Taipei Medical University Hospital (103TMU-TMUH-09), Taipei Medical University (TMU102-AE1-B03), and the Top University Project- Cancer Translational Center of Taipei Medical University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Health Promotion Administration MOHAW. Health indicator 123. https://olap.hpa.gov.tw/en_US/index.aspx. Accessed May 5 2016
  2. 2.
    Moller S, Mucci LA, Harris JR et al (2016) The heritability of breast cancer among women in the nordic twin study of cancer. Cancer Epidemiol Biomark Prev 25:145–150CrossRefGoogle Scholar
  3. 3.
    Cai Q, Long J, Lu W et al (2011) Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. Hum Mol Genet 20:4991–4999CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gold B, Kirchhoff T, Stefanov S et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci USA 105:4340–4345CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hunter DJ, Kraft P, Jacobs KB et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kim HC, Lee JY, Sung H et al (2012) A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res 14:R56CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Long J, Cai Q, Sung H et al (2012) Genome-wide association study in East Asians identifies novel susceptibility loci for breast cancer. PLoS Genet 8:e1002532CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Stacey SN, Manolescu A, Sulem P et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869CrossRefPubMedGoogle Scholar
  10. 10.
    Stacey SN, Manolescu A, Sulem P et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706CrossRefPubMedGoogle Scholar
  11. 11.
    Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M (2010) Genetic susceptibility to breast cancer. Mol Oncol 4:174–191CrossRefPubMedGoogle Scholar
  12. 12.
    Peto J, Collins N, Barfoot R et al (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91:943–949CrossRefPubMedGoogle Scholar
  13. 13.
    Pharoah PD, Dunning AM, Ponder BA, Easton DF (2004) Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer 4:850–860CrossRefPubMedGoogle Scholar
  14. 14.
    Mavaddat N, Pharoah PD, Michailidou K et al (2015) Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst 107:djv036CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Warren Andersen S, Trentham-Dietz A, Gangnon RE et al (2013) The associations between a polygenic score, reproductive and menstrual risk factors and breast cancer risk. Breast Cancer Res Treat 140:427–434CrossRefPubMedGoogle Scholar
  16. 16.
    Reeves GK, Travis RC, Green J et al (2010) Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci. JAMA 304:426–434CrossRefPubMedGoogle Scholar
  17. 17.
    Hsieh YC, Hung CT, Lien LM et al (2009) A significant decrease in blood pressure through a family-based nutrition health education programme among community residents in Taiwan. Public Health Nutr 12(4):570–577CrossRefPubMedGoogle Scholar
  18. 18.
    Long J, Cai Q, Shu XO et al (2010) Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium. PLoS Genet 6:e1001002CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hein R, Maranian M, Hopper JL et al (2012) Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC). PLoS ONE 7:e42380CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Shu XO, Long J, Lu W et al (2012) Novel genetic markers of breast cancer survival identified by a genome-wide association study. Cancer Res 72:1182–1189CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zheng W, Wen W, Gao YT et al (2010) Genetic and clinical predictors for breast cancer risk assessment and stratification among Chinese women. J Natl Cancer Inst 102(13):972–981CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zheng W, Zhang B, Cai Q et al (2013) 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 22(12):2539–2550CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Steyerberg EW, Harrell FE Jr, Borsboom GJ et al (2001) Internal validation of predictive models: efficiency of some procedures for logistic regression analysis. J Clin Epidemiol 54(8):774–781CrossRefPubMedGoogle Scholar
  24. 24.
    Efron B, Tibshirani R (1997) Improvements on cross-validation: the 632+ bootstrap method. J Am Stat Assoc 92:548–560Google Scholar
  25. 25.
    Harlid S, Ivarsson MI, Butt S et al (2012) Combined effect of low-penetrant SNPs on breast cancer risk. Br J Cancer 106:389–396CrossRefPubMedGoogle Scholar
  26. 26.
    Sueta A, Ito H, Kawase T 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 132:711–721CrossRefPubMedGoogle Scholar
  27. 27.
    Huang CS, Lin CH, Lu YS, Shen CY (2010) Unique features of breast cancer in Asian women–breast cancer in Taiwan as an example. J Steroid Biochem Mol Biol 118:300–303CrossRefPubMedGoogle Scholar
  28. 28.
    Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129CrossRefPubMedGoogle Scholar
  29. 29.
    Cui F, Wu D, Wang W, He X, Wang M (2016) Variants of FGFR2 and their associations with breast cancer risk: a HUGE systematic review and meta-analysis. Breast Cancer Res Treat 155:313–335CrossRefPubMedGoogle Scholar
  30. 30.
    Klinge CM, Blankenship KA, Risinger KE et al (2005) Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem 280:7460–7468CrossRefPubMedGoogle Scholar
  31. 31.
    Zheng Q, Ye J, Wu H, Yu Q, Cao J (2014) Association between mitogen-activated protein kinase kinase kinase 1 polymorphisms and breast cancer susceptibility: a meta-analysis of 20 case-control studies. PLoS ONE 9:e90771CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yu Y, Chen Z, Wang H, Zhang Y (2013) Quantitative assessment of common genetic variants on chromosome 5p12 and hormone receptor status with breast cancer risk. PLoS ONE 8:e72154CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liang H, Li H, Yang X et al (2016) Associations of genetic variants at nongenic susceptibility loci with breast cancer risk and heterogeneity by tumor subtype in Southern Han Chinese Women. Biomed Res Int 2016:3065493PubMedPubMedCentralGoogle Scholar
  34. 34.
    Han W, Woo JH, Yu JH et al (2011) Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomark Prev 20:793–798CrossRefGoogle Scholar
  35. 35.
    Long J, Shu XO, Cai Q et al (2010) Evaluation of breast cancer susceptibility loci in Chinese women. Cancer Epidemiol Biomark Prev 19:2357–2365CrossRefGoogle Scholar
  36. 36.
    Wadt KA, Aoude LG, Golmard L et al (2015) Germline RAD51B truncating mutation in a family with cutaneous melanoma. Fam Cancer 14:337–340CrossRefPubMedGoogle Scholar
  37. 37.
    Chan M, Ji SM, Liaw CS et al (2012) Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population. Breast Cancer Res Treat 136:209–220CrossRefPubMedGoogle Scholar
  38. 38.
    Wacholder S, Hartge P, Prentice R et al (2010) Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362(11):986–993CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hüsing A, Canzian F, Beckmann L et al (2012) Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status. J Med Genet 49:601–608CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yi-Chen Hsieh
    • 1
  • Shih-Hsin Tu
    • 2
    • 3
    • 4
  • Chien-Tien Su
    • 5
    • 6
  • Er-Chieh Cho
    • 7
  • Chih-Hsiung Wu
    • 8
  • Mao-Chih Hsieh
    • 9
  • Shiyng-Yu Lin
    • 6
  • Yun-Ru Liu
    • 10
  • Chin-Sheng Hung
    • 2
    • 3
    • 4
    Email author
  • Hung-Yi Chiou
    • 11
    Email author
  1. 1.Graduate Institute of Neural Regenerative Medicine, College of Medical Science and TechnologyTaipei Medical UniversityTaipeiTaiwan
  2. 2.Department of Surgery, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  3. 3.Taipei Cancer CenterTaipei Medical UniversityTaipeiTaiwan
  4. 4.Breast Medical CenterTaipei Medical University HospitalTaipeiTaiwan
  5. 5.School of Public Health, College of Public Health and NutritionTaipei Medical UniversityTaipeiTaiwan
  6. 6.Department of Family Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  7. 7.Department of Clinical Pharmacy, School of Pharmacy, College of PharmacyTaipei Medical UniversityTaipeiTaiwan
  8. 8.Department of SurgeryTaipei Medical University-Shuang Ho HospitalTaipeiTaiwan
  9. 9.Department of SurgeryTaipei Medical University-Wan Fang HospitalTaipeiTaiwan
  10. 10.Joint Biobank, Office of Human ResearchTaipei Medical UniversityTaipeiTaiwan
  11. 11.School of Public Health, College of Public Health and NutritionTaipei Medical UniversityTaipeiTaiwan

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