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A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

RecQ helicases play a central role in maintaining genome stability and may interact with some important cancer-related proteins such as BRCA1. Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature aging and cancer predisposition, including breast cancer. In this case–control study of 1,004 breast cancer cases and 1,008 controls, we tested the hypothesis that non-conservative amino acid exchanges in WRN (leu1074Phe), BLM (Met298Thr) and BRCA1 (Pro871Leu) are independently or jointly associated with the risk of breast cancer in Chinese women. We found that the variant genotype of WRN Leu1074Phe was associated with a 1.36-fold significantly increased risk of breast cancer (OR = 1.36, 95% CI = 1.06–1.74). Moreover, a significant gene–environment interaction was evident between WRN leu1074Phe and age at menarche (P int = 0.02). Subjects carrying Phe/Phe genotype and with earlier age at menarche had 3.58-fold increased risk of breast cancer (OR = 3.58, 95% CI = 2.54–5.05). However, we did not find the significant main effect of polymorphisms in BLM and BRCA1 and also no locus–locus interactions were identified between WRN, BLM and BRCA1. These findings indicate that WRN leu1074Phe variant may contribute to the susceptibility of breast cancer in Chinese women.

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Abbreviations

WRN :

Werner syndrome

BLM :

Bloom syndrome

ER:

Estrogen receptor

PR:

Progesterone receptor

SNP:

Single nucleotide polymorphism

OR:

Odds-ratio

CI:

Confidence interval

References

  1. Sharma S, Brosh RM Jr (2007) Human RECQ1 is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS One 2:e1297. doi:10.1371/journal.pone.0001297

  2. Chakraverty RK, Hickson ID (1999) Defending genome integrity during DNA replication: a proposed role for RecQ family helicases. Bioessays 21:286–294. doi:10.1002/(SICI)1521-1878(199904)21:4<286::AID-BIES4>3.0.CO;2-Z

    Article  CAS  PubMed  Google Scholar 

  3. Karow JK, Wu L, Hickson ID (2000) RecQ family helicases: roles in cancer and aging. Curr Opin Genet Dev 10:32–38. doi:10.1016/S0959-437X(99)00039-8

    Article  CAS  PubMed  Google Scholar 

  4. van Brabant AJ, Stan R, Ellis NA (2000) DNA helicases, genomic instability, and human genetic disease. Annu Rev Genomics Hum Genet 1:409–459. doi:10.1146/annurev.genom.1.1.409

    Article  PubMed  Google Scholar 

  5. Mohaghegh P, Hickson ID (2001) DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum Mol Genet 10:741–746. doi:10.1093/hmg/10.7.741

    Article  CAS  PubMed  Google Scholar 

  6. Cheng WH, Kusumoto R, Opresko PL, Sui X, Huang S, Nicolette ML, Paull TT, Campisi J, Seidman M, Bohr VA (2006) Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links. Nucleic Acids Res 34:2751–2760. doi:10.1093/nar/gkl362

    Article  CAS  PubMed  Google Scholar 

  7. Futaki M, Liu JM (2001) Chromosomal breakage syndromes and the BRCA1 genome surveillance complex. Trends Mol Med 7:560–565. doi:10.1016/S1471-4914(01)02178-5

    Article  CAS  PubMed  Google Scholar 

  8. Kamath-Loeb AS, Welcsh P, Waite M, Adman ET, Loeb LA (2004) The enzymatic activities of the Werner syndrome protein are disabled by the amino acid polymorphism R834C. J Biol Chem 279:55499–55505. doi:10.1074/jbc.M407128200

    Article  CAS  PubMed  Google Scholar 

  9. Ogata N, Shiraki M, Hosoi T, Koshizuka Y, Nakamura K, Kawaguchi H (2001) A polymorphic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal women. J Bone Miner Metab 19:296–301. doi:10.1007/s007740170013

    Article  CAS  PubMed  Google Scholar 

  10. Ye L, Miki T, Nakura J, Oshima J, Kamino K, Rakugi H, Ikegami H, Higaki J, Edland SD, Martin GM, Ogihara T (1997) Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population. Am J Med Genet 68:494–498. doi:10.1002/(SICI)1096-8628(19970211)68:4<494::AID-AJMG30>3.0.CO;2-L

    Article  CAS  PubMed  Google Scholar 

  11. Wirtenberger M, Frank B, Hemminki K, Klaes R, Schmutzler RK, Wappenschmidt B, Meindl A, Kiechle M, Arnold N, Weber BH, Niederacher D, Bartram CR, Burwinkel B (2006) Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer. Carcinogenesis 27:1655–1660. doi:10.1093/carcin/bgi374

    Article  CAS  PubMed  Google Scholar 

  12. Kohno T, Sakiyama T, Kunitoh H, Goto K, Nishiwaki Y, Saito D, Hirose H, Eguchi T, Yanagitani N, Saito R, Sasaki-Matsumura R, Mimaki S, Toyama K, Yamamoto S, Kuchiba A, Sobue T, Ohta T, Ohki M, Yokota J (2006) Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk. Carcinogenesis 27:2448–2454. doi:10.1093/carcin/bgl095

    Article  CAS  PubMed  Google Scholar 

  13. Kerr P, Ashworth A (2001) New complexities for BRCA1 and BRCA2. Curr Biol 11:R668–R676. doi:10.1016/S0960-9822(01)00389-X

    Article  CAS  PubMed  Google Scholar 

  14. Welcsh PL, King MC (2001) BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 10:705–713. doi:10.1093/hmg/10.7.705

    Article  CAS  PubMed  Google Scholar 

  15. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182. doi:10.1016/S0092-8674(02)00615-3

    Article  CAS  PubMed  Google Scholar 

  16. Eisen A, Lubinski J, Gronwald J, Moller P, Lynch HT, Klijn J, Kim-Sing C, Neuhausen SL, Gilbert L, Ghadirian P, Manoukian S, Rennert G, Friedman E, Isaacs C, Rosen E, Rosen B, Daly M, Sun P, Narod SA (2008) Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 100:1361–1367. doi:10.1093/jnci/djn313

    Article  CAS  PubMed  Google Scholar 

  17. Ke X, Collins A, Ye S (2001) PIRA PCR designer for restriction analysis of single nucleotide polymorphisms. Bioinformatics 17:838–839. doi:10.1093/bioinformatics/17.9.838

    Article  CAS  PubMed  Google Scholar 

  18. Armes JE, Hammet F, de Silva M, Ciciulla J, Ramus SJ, Soo WK, Mahoney A, Yarovaya N, Henderson MA, Gish K, Hutchins AM, Price GR, Venter DJ (2004) Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers. Oncogene 23:5697–5702. doi:10.1038/sj.onc.1207740

    Article  CAS  PubMed  Google Scholar 

  19. Bachrati CZ, Hickson ID (2003) RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem J 374:577–606. doi:10.1042/BJ20030491

    Article  CAS  PubMed  Google Scholar 

  20. von Kobbe C, Bohr VA (2002) A nucleolar targeting sequence in the Werner syndrome protein resides within residues 949–1092. J Cell Sci 115:3901–3907. doi:10.1242/jcs.00076

    Article  Google Scholar 

  21. Castro E, Edland SD, Lee L, Ogburn CE, Deeb SS, Brown G, Panduro A, Riestra R, Tilvis R, Louhija J, Penttinen R, Erkkola R, Wang L, Martin GM, Oshima J (2000) Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet 95:374–380. doi:10.1002/1096-8628(20001211)95:4<374::AID-AJMG14>3.0.CO;2-4

    Article  CAS  PubMed  Google Scholar 

  22. Hirai M, Suzuki S, Hinokio Y, Yamada T, Yoshizumi S, Suzuki C, Satoh J, Oka Y (2005) WRN gene 1367 Arg allele protects against development of type 2 diabetes mellitus. Diabetes Res Clin Pract 69:287–292. doi:10.1016/j.diabres.2005.01.012

    Article  CAS  PubMed  Google Scholar 

  23. Ding SL, Yu JC, Chen ST, Hsu GC, Shen CY (2007) Genetic variation in the premature aging gene WRN: a case–control study on breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 16:263–269. doi:10.1158/1055-9965.EPI-06-0678

    Article  CAS  PubMed  Google Scholar 

  24. Durocher F, Shattuck-Eidens D, McClure M, Labrie F, Skolnick MH, Goldgar DE, Simard J (1996) Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum Mol Genet 5:835–842. doi:10.1093/hmg/5.6.835

    Article  CAS  PubMed  Google Scholar 

  25. Dunning AM, Chiano M, Smith NR, Dearden J, Gore M, Oakes S, Wilson C, Stratton M, Peto J, Easton D, Clayton D, Ponder BA (1997) Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum Mol Genet 6:285–289. doi:10.1093/hmg/6.2.285

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the Program for Changjiang Scholars and Innovative Research Team in University (IRT0631); National Key Basic Research Program Grants 2002CB512908; Jiangsu Society Development Foundation: BS2006006.

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Authors and Affiliations

  1. Laboratory of Reproductive Medicine, Nanjing Medical University, 210029, Nanjing, China

    Zhanwei Wang, Yan Xu, Hongxia Ma, Zhibin Hu, Xinru Wang & Hongbing Shen

  2. Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, 210029, Nanjing, China

    Zhanwei Wang, Zhibin Hu & Hongbing Shen

  3. Department of General Surgery, Jiangsu Cancer Hospital, 210029, Nanjing, China

    Jinhai Tang & Jianwei Qin

  4. Nanjing Maternity and Child Health Hospital, Nanjing Medical University, 210029, Nanjing, China

    Chen Lu

  5. Department of General Surgery, Nanjing Gulou Hospital, 210029, Nanjing, China

    Xuechen Wang

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  1. Zhanwei Wang
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  2. Yan Xu
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  3. Jinhai Tang
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  7. Xuechen Wang
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  9. Xinru Wang
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  10. Hongbing Shen
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Corresponding author

Correspondence to Hongbing Shen.

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Wang, Z., Xu, Y., Tang, J. et al. A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women. Breast Cancer Res Treat 118, 169–175 (2009). https://doi.org/10.1007/s10549-009-0327-z

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  • DOI: https://doi.org/10.1007/s10549-009-0327-z

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