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Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years

  • Epidemiology
  • Published:
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Abstract

The histone protein family member X (H2AFX) is important in maintaining chromatin structure and genetic stability. Genetic variants in H2AFX may alter protein functions and thus cancer risk. In this case-control study, we genotyped four common single nucleotide polymorphisms (i.e., −1654A > G [rs643788], −1420G > A [rs8551], and −1187T > C [rs7759] in the H2AFX promoter region and 1057C > T [rs7350] in the 3′ untranslated region (UTR)) in 467 patients with sporadic breast cancer and 488 cancer-free controls. All female subjects were non-Hispanic whites aged ≤55 years. We found that significantly increased risk of breast cancer was associated with variant genotypes in the H2AFX promoter: adjusted odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.38–2.34 for −1654AG/GG; OR = 1.40, 95% CI = 1.07–1.83 for −1420GA/AA; and OR = 1.65, 95% CI = 1.26–2.16 for −1187TC/CC. Furthermore, the number of variant alleles in the promoter haplotypes was associated with increased risks of breast cancer in a dose-response manner (OR = 6.08, 95% CI = 3.25–11.38; OR = 6.83, 95% CI = 3.83–12.18; and OR = 23.61, 95% CI = 3.95–140.99 for one, two, and three variant alleles, respectively) (P trend < 0.0001). Age at onset of breast cancer significantly decreased as the number of variant alleles increased (P trend = 0.024). However, these effects were not observed in the 3′UTR 1057C > T polymorphism. Therefore, we believe that H2AFX promoter polymorphisms may contribute to the etiology of sporadic breast cancer in young non-Hispanic white women. Larger association studies and related functional studies are warranted to confirm these findings.

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Abbreviations

CI:

Confidence interval

DSB:

Double-strand break

LD:

Linkage disequilibrium

H2AFX:

H2A histone familymember X

OR:

Odds ratio

PCR-RFLP:

Polymerase chain reaction-restriction fragment length polymorphism

SNP:

Single nucleotide polymorphism

UTR:

Untranslated region

Reference

  1. Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389:251–260

    Article  PubMed  CAS  Google Scholar 

  2. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273:5858–5868

    Article  PubMed  CAS  Google Scholar 

  3. Ivanova VS, Hatch CL, Bonner WM (1994) Characterization of the human histone H2A.X gene. Comparison of its promoter with other H2A gene promoters. J Biol Chem 269:24189–24194

    PubMed  CAS  Google Scholar 

  4. Ivanova VS, Zimonjic D, Popescu N, Bonner WM (1994) Chromosomal localization of the human histone H2A.X gene to 11q23.2-q23.3 by fluorescence in situ hybridization. Hum Genet 94:303–306

    Article  PubMed  CAS  Google Scholar 

  5. Bassing CH, Chua KF, Sekiguchi J, Suh H, Whitlow SR, Fleming JC, Monroe BC, Ciccone DN, Yan C, Vlasakova K, Livingston DM, Ferguson DO, Scully R, Alt FW (2002) Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci USA 99:8173–8178

    Article  PubMed  CAS  Google Scholar 

  6. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A (2002) Genomic instability in mice lacking histone H2AX. Science 296:922–927

    Article  PubMed  CAS  Google Scholar 

  7. Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A (2003) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114:371–383

    Article  PubMed  CAS  Google Scholar 

  8. Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW (2003) Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114:359–370

    Article  PubMed  CAS  Google Scholar 

  9. Ralhan R, Kaur J, Kreienberg R, Wiesmuller L (2007) Links between DNA double strand break repair and breast cancer: accumulating evidence from both familial and nonfamilial cases. Cancer Lett 248:1–17

    Article  PubMed  CAS  Google Scholar 

  10. Zhang C, Naftalis E, Euhus D (2006) Carcinogen-induced DNA double strand break repair in sporadic breast cancer. J Surg Res 135:120–128

    Article  PubMed  CAS  Google Scholar 

  11. Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27:247–254

    Article  PubMed  CAS  Google Scholar 

  12. Abbott DW, Freeman ML, Holt JT (1998) Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 90:978–985

    Article  PubMed  CAS  Google Scholar 

  13. Rosen EM, Fan S, Pestell RG, Goldberg ID (2003) BRCA1 gene in breast cancer. J Cell Physiol 196:19–41

    Article  PubMed  CAS  Google Scholar 

  14. Ting NS, Lee WH (2004) The DNA double-strand break response pathway: becoming more BRCAish than ever. DNA Repair (Amst) 3:935–944

    Article  CAS  Google Scholar 

  15. Little JB (2000) Radiation carcinogenesis. Carcinogenesis 21:397–404

    Article  PubMed  CAS  Google Scholar 

  16. Vilenchik MM, Knudson AG (2003) Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci USA 100:12871–12876

    Article  PubMed  CAS  Google Scholar 

  17. Kaufmann WK, Filatov L, Oglesbee SE, Simpson DA, Lotano MA, McKeen HD, Sawyer LR, Moore DT, Millikan RC, Cordeiro-Stone M, Carey LA (2006) Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk. Carcinogenesis 27:2519–2527

    Article  PubMed  CAS  Google Scholar 

  18. Lu J, Wei Q, Bondy ML, Li D, Brewster A, Shete S, Yu TK, Sahin A, Meric-Bernstam F, Hunt KK, Singletary SE, Ross MI, Wang LE (2006) Polymorphisms and haplotypes of the NBS1 gene are associated with risk of sporadic breast cancer in non-Hispanic white women < = 55 years. Carcinogenesis 27:2209–2216

    Article  PubMed  CAS  Google Scholar 

  19. Shi Q, Wang LE, Bondy ML, Brewster A, Singletary SE, Wei Q (2004) Reduced DNA repair of benzo[a]pyrene diol epoxide-induced adducts and common XPD polymorphisms in breast cancer patients. Carcinogenesis 25:1695–1700

    Article  PubMed  CAS  Google Scholar 

  20. Xiong P, Bondy ML, Li D, Shen H, Wang LE, Singletary SE, Spitz MR, Wei Q (2001) Sensitivity to benzo(a)pyrene diol-epoxide associated with risk of breast cancer in young women and modulation by glutathione S-transferase polymorphisms: a case-control study. Cancer Res 61:8465–8469

    PubMed  CAS  Google Scholar 

  21. Monteiro AN, Zhang S, Phelan CM, Narod SA (2003) Absence of constitutional H2AX gene mutations in 101 hereditary breast cancer families. J Med Genet 40:e51

    Article  PubMed  CAS  Google Scholar 

  22. Walsh SH, Rosenquist R (2005) Absence of H2AX gene mutations in B-cell leukemias and lymphomas. Leukemia 19:464

    Article  PubMed  CAS  Google Scholar 

  23. Wilkie GS, Dickson KS, Gray NK (2003) Regulation of mRNA translation by 5′- and 3′-UTR-binding factors. Trends Biochem Sci 28:182–188

    Article  PubMed  CAS  Google Scholar 

  24. Buckland PR, Hoogendoorn B, Coleman SL, Guy CA, Smith SK, O’Donovan MC (2005) Strong bias in the location of functional promoter polymorphisms. Hum Mutat 26:214–223

    Article  PubMed  CAS  Google Scholar 

  25. Ponomarenko JV, Merkulova TI, Vasiliev GV, Levashova ZB, Orlova GV, Lavryushev SV, Fokin ON, Ponomarenko MP, Frolov AS, Sarai A (2001) rSNP_Guide, a database system for analysis of transcription factor binding to target sequences: application to SNPs and site-directed mutations. Nucleic Acids Res 29:312–316

    Article  PubMed  CAS  Google Scholar 

  26. Buckland PR (2006) The importance and identification of regulatory polymorphisms and their mechanisms of action. Biochim Biophys Acta 1762:17–28

    PubMed  CAS  Google Scholar 

  27. De Gobbi M, Viprakasit V, Hughes JR, Fisher C, Buckle VJ, Ayyub H, Gibbons RJ, Vernimmen D, Yoshinaga Y, de Jong P, Cheng JF, Rubin EM, Wood WG, Bowden D, Higgs DR (2006) A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 312:1215–1217

    Article  PubMed  CAS  Google Scholar 

  28. Novik KL, Spinelli JJ, Macarthur AC, Shumansky K, Sipahimalani P, Leach S, Lai A, Connors JM, Gascoyne RD, Gallagher RP, Brooks-Wilson AR (2007) Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 16:1098–1106

    Article  PubMed  CAS  Google Scholar 

  29. Vogt PK (2001) Jun, the oncoprotein. Oncogene 20:2365–2377

    Article  PubMed  CAS  Google Scholar 

  30. Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ (2006) c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer. Hum Pathol 37:668–674

    Article  PubMed  CAS  Google Scholar 

  31. Whelan J, Cordle SR, Henderson E, Weil PA, Stein R (1990) Identification of a pancreatic beta-cell insulin gene transcription factor that binds to and appears to activate cell-type-specific expression: its possible relationship to other cellular factors that bind to a common insulin gene sequence. Mol Cell Biol 10:1564–1572

    PubMed  CAS  Google Scholar 

  32. Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5:153–165

    Article  PubMed  CAS  Google Scholar 

  33. Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE (2006) Increased prevalence of prior breast cancer in women with newly diagnosed diabetes. Breast Cancer Res Treat 98:303–309

    Article  PubMed  Google Scholar 

  34. Colditz GA, Rosner BA, Chen WY, Holmes MD, Hankinson SE (2004) Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst 96:218–228

    Article  PubMed  CAS  Google Scholar 

  35. Grann VR, Troxel AB, Zojwalla NJ, Jacobson JS, Hershman D, Neugut AI (2005) Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer 103:2241–2251

    Article  PubMed  CAS  Google Scholar 

  36. Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, D’Cruz CM, Chodosh LA (2006) Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res 66:6421–6431

    Article  PubMed  CAS  Google Scholar 

  37. Li SL, Schlegel W, Valente AJ, Clark RA (1999) Critical flanking sequences of PU.1 binding sites in myeloid-specific promoters. J Biol Chem 274:32453–32460

    Article  PubMed  CAS  Google Scholar 

  38. Marecki S, McCarthy KM, Nikolajczyk BS (2004) PU.1 as a chromatin accessibility factor for immunoglobulin genes. Mol Immunol 40:723–731

    Article  PubMed  CAS  Google Scholar 

  39. Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG (2002) Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood 100:998–1007

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported in part by National Institutes of Health grants CA 108364 (L.E.W.), ES11740 (Q.W.), and CA 16672 (M. D. Anderson Cancer Center). We thank Margaret Lung and Leanel Fairly for their assistance in recruiting the subjects; Luo Wang, Ping Xiong, Yawei Qiao, Kejing Xu, Zhensheng Liu, Zhaozheng Guo, Jianzhong He, and Yinyan Li for their laboratory assistance; and Ann Sutton for scientific editing.

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Author notes

  1. Jiachun Lu

    Present address: The Institute for Chemical Carcinogenesis, Guangzhou Medical College, 195 Dongfengxi Rd., Guangzhou, Guangdong, P.R. China

Authors and Affiliations

  1. Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Jiachun Lu, Qingyi Wei, Melissa L. Bondy & Li-E Wang

  2. Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Abenaa M. Brewster & Therese B. Bevers

  3. Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Tse-Kuan Yu & Thomas A. Buchholz

  4. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Funda Meric-Bernstam, Kelly K. Hunt & S. Eva Singletary

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  1. Jiachun Lu
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Correspondence to Li-E Wang.

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Lu, J., Wei, Q., Bondy, M.L. et al. Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years. Breast Cancer Res Treat 110, 357–366 (2008). https://doi.org/10.1007/s10549-007-9717-2

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