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Prognostic value of single nucleotide polymorphisms of candidate genes associated with inflammation in early stage breast cancer

  • Epidemiology
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Abstract

To examine the role of germline genetic variations in inflammatory pathways as modifiers of time to recurrence (TTR) in patients with early stage breast cancer (BC), DNA from 997 early stage BC patients was genotyped for 53 tagging single nucleotide polymorphisms (SNPs) in 12 genes involved in inflammation. SNPs were analyzed separately for Caucasians versus African-Americans and Hispanics. Cox proportional hazards models were used to evaluate the association between SNPs in the inflammatory genes and TTR, adjusted for clinical and pathologic covariates. In univariable analyses of Caucasian women, the homozygous genotype of 12 SNPs, including 6 NFKB1 SNPs, 4 IL4 SNPs, and 2 IL13 SNPs, were significantly associated with a decrease in TTR compared with the heterozygous and/or corresponding homozygous genotype (P < 0.05). The significant NFKB1 and IL4 SNPs were in an area of high linkage disequilibrium (D′ > 0.8). After adjusting for stage, age, and treatment, carriage of the homozygous genotypes for NFKB1 rs230532 and IL13rs1800925 were independently associated with a shorter TTR (P = 0.001 and P = 0.034, respectively). In African-American and Hispanic patients, expression of NFKB1 rs3774932, TNFrs1799964, and IL4rs3024543 SNPs were associated with a shorter TTR in univariable model. Only NFKB1 rs3774932 (P = 0.02) and IL4Rrs3024543 (P = 0.03) had independent prognostic value in the multivariable model These data support the existence of host genetic susceptibility as a component in recurrence risk mediated by pro-inflammatory and immune factors, and suggest the potential for drugs which modify immune responses and inflammatory genes to improve prognosis in early stage BC.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249

    Article  PubMed  Google Scholar 

  2. Brewster AM, Hortobagyi GN, Broglio KR, Kau SW, Santa-Maria CA, Arun B et al (2008) Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst 100(16):1179–1183

    Article  PubMed  Google Scholar 

  3. Cianfrocca M, Goldstein LJ (2004) Prognostic and predictive factors in early-stage breast cancer. Oncologist 9(6):606–616

    Article  PubMed  Google Scholar 

  4. Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K, Spyratos F, Brunet M (1989) Prognostic value of histologic grade nuclear components of Scarff–Bloom–Richardson (SBR). An improved score modification based on a multivariate analysis of 1,262 invasive ductal breast carcinomas. Cancer 64(9):1914–1921

    Article  PubMed  Google Scholar 

  5. Hess KR, Pusztai L, Buzdar AU, Hortobagyi GN (2003) Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat 78(1):105–118

    Article  PubMed  CAS  Google Scholar 

  6. Menard S, Fortis S, Castiglioni F, Agresti R, Balsari A (2001) HER2 as a prognostic factor in breast cancer. Oncology 61(Suppl 2):67–72

    PubMed  CAS  Google Scholar 

  7. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874

    Article  PubMed  CAS  Google Scholar 

  8. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752

    Article  PubMed  CAS  Google Scholar 

  9. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K et al (2004) Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2(2):E7

    Article  PubMed  Google Scholar 

  10. Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C (2007) An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 8(8):R157

    Article  PubMed  Google Scholar 

  11. Yau C, Esserman L, Moore DH, Waldman F, Sninsky J, Benz CC (2010) A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer. Breast Cancer Res 12(5):R85

    Article  PubMed  Google Scholar 

  12. Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK et al (2010) Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 28(28):4316–4323

    Article  PubMed  Google Scholar 

  13. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444

    Article  PubMed  CAS  Google Scholar 

  14. Le Marchand L, Haiman CA, van den Berg D, Wilkens LR, Kolonel LN, Henderson BE (2004) T29C polymorphism in the transforming growth factor beta1 gene and postmenopausal breast cancer risk: the Multiethnic Cohort Study. Cancer Epidemiol Biomarkers Prev 13(3):412–415

    PubMed  Google Scholar 

  15. Smith KC, Bateman AC, Fussell HM, Howell WM (2004) Cytokine gene polymorphisms and breast cancer susceptibility and prognosis. Eur J Immunogenet 31(4):167–173

    Article  PubMed  CAS  Google Scholar 

  16. Balasubramanian SP, Azmy IA, Higham SE, Wilson AG, Cross SS, Cox A et al (2006) Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review. BMC Cancer 14(6):188

    Article  Google Scholar 

  17. Kim S, Hagemann A, DeMichele A (2009) Immuno-modulatory gene polymorphisms and outcome in breast and ovarian cancer. Immunol Invest 38(3–4):324–340

    Article  PubMed  CAS  Google Scholar 

  18. Brewster AM, Do K-A, Thompson PA, Hahn KM, Sahin AA, Cao Y, Stewart MM, Murray JL, Hortobagyi GN, Bondy ML (2008) The relationship between epidemiological risk factors and breast cancer recurrence. J Clin Oncol 25(28):4438–4444

    Article  Google Scholar 

  19. Pounds S, Morris SW (2003) Estimating the occurrence of false positive and false negatives in microarray studies by approximating and partitioning the empirical distribution of p-values. Bioinformatics 19:1236–1242

    Article  PubMed  CAS  Google Scholar 

  20. Binder H, Schumacher M (2008) Allowing for mandatory covariates in boosting estimation of sparse high-dimensional survival models. BMC Bioinformatics 9:1–10

    Article  Google Scholar 

  21. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265

    Article  PubMed  CAS  Google Scholar 

  22. Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96

    Article  PubMed  CAS  Google Scholar 

  23. Nakshatri H, Goulet RJ Jr (2002) NF-kappaB and breast cancer. Curr Probl Cancer 26(5):282–309

    Article  PubMed  Google Scholar 

  24. Nelson DE, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE et al (2004) Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 306(5696):704–708

    Article  PubMed  CAS  Google Scholar 

  25. Barkett M, Gilmore TD (1999) Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 18(49):6910–6924

    Article  PubMed  CAS  Google Scholar 

  26. Kurt RA, Urba WJ, Smith JW, Schoof DD (1998) Peripheral T lymphocytes from women with breast cancer exhibit abnormal protein expression of several signaling molecules. Int J Cancer 78:16–20

    Article  PubMed  CAS  Google Scholar 

  27. Baumgarten SC, Frasor J (2012) Minireview: inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol 26(3):360–371

    Article  PubMed  CAS  Google Scholar 

  28. Hageman T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) “Re-educating” tumor-associated macrophages by targeting NF-kB. J Exp Med 206:1261–1268

    Article  Google Scholar 

  29. Kelly PM, Davison RS, Bliss E (1988) McGee J0. Macrophages in human breast disease: a quantitative immunohistochemical study. Br J Cancer 57:174–177

    Article  PubMed  CAS  Google Scholar 

  30. Biswas DK, Shi Q, Baily S, Strickland I, Ghosh S, Pardee AB et al (2004) NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci USA 101(27):10137–10142

    Article  PubMed  CAS  Google Scholar 

  31. Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Sledge GW (1997) Constitutive activation of NF-kB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629–3639

    PubMed  CAS  Google Scholar 

  32. de Graffenried LA, Chandrasekar B, Friedrichs WE, Donzis E, Silva J, Hidalgo M, Freeman JW, Weiss GR (2004) NF-kB inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to Tamoxifen. Ann Oncol 15:885–890

    Article  Google Scholar 

  33. Riggins RB, Zwart A, Nehra R, Clarke R (2005) The nuclear factor kB inhibitor parthenolide restores ICI 182,780 (Fasolodex, fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol Cancer Ther 4:33–41

    Article  PubMed  CAS  Google Scholar 

  34. Van Dyke AL, Cote ML, Wenzlaff AS, Land S, Schwartz AG (2009) Cytokine SNPs: comparison of allele frequencies by race and implications for future studies. Cytokine 46(2):236–244

    Article  PubMed  Google Scholar 

  35. Erdei E, Kang H, Meisner A, White K, Pickett G, Baca C, Royce M, Berwick M (2010) Polymorphisms in cytokine genes and serum cytokine levels among New Mexican Women with and without breast cancer. Cytokine 51:18–24

    Article  PubMed  CAS  Google Scholar 

  36. De Nardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 2(4):212

    Google Scholar 

  37. Schoof N, von Bonin F, Zeynalova S, Ziepert M, Jung W, Loeffler M, Pfreundschuh M, Trumper L, Kube D (2009) Favorable impact of the interleukin-4 receptor allelic variant I75 on the survival of diffuse large B-cell lymphoma patients demonstrated in a large prospective clinical trial. Ann Oncol 20(9):1548–1554

    Article  PubMed  CAS  Google Scholar 

  38. Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D et al (2007) Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J Exp Med 204(5):1037–1047

    Article  PubMed  CAS  Google Scholar 

  39. Martin AM, Athanasiadis G, Greshock JD, Fisher J, Lux MP, Calzone K et al (2003) Population frequencies of single nucleotide polymorphisms (SNPs) in immuno-modulatory genes. Hum Hered 55(4):171–178

    Article  PubMed  CAS  Google Scholar 

  40. Haukim N, Bidwell JL, Smith AJ, Keen LJ, Gallagher G, Kimberly R et al (2002) Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 3(6):313–330

    Article  PubMed  CAS  Google Scholar 

  41. Guida E, Stewart A (1998) Influence of hypoxia and glucose deprivation on tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor expression in human cultured monocytes. Cell Physiol Biochem 8(1–2):75–88

    Article  PubMed  CAS  Google Scholar 

  42. Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR (1994) Expression of tumour necrosis factor (TNF alpha) and its receptors in benign and malignant breast tissue. Int J Cancer 56(6):777–782

    Article  PubMed  CAS  Google Scholar 

  43. Jung JH, Chae YS, Moon JH, Kang BW, Kim JG, Sohn SK, Park JY, Lee MH, Park HY (2010) TNF superfamily gene polymorphism as prognostic factor in early breast cancer. J Cancer Res Clin Oncol 136(5):685–694

    Article  PubMed  CAS  Google Scholar 

  44. Mestiri S, Bouaouina N, Ahmed SB, Khedhaier A, Jrad BB, Remadi S et al (2001) Genetic variation in the tumor necrosis factor-alpha promoter region and in the stress protein hsp70-2: susceptibility and prognostic implications in breast carcinoma. Cancer 91(4):672–678

    Article  PubMed  CAS  Google Scholar 

  45. Pusztai L, Mendoza TR, Reuben JM, Martinez MM, Willey JS, Lara J, Syed A, Fritsche HA, Bruera E, Booser D, Valero V, Arun B, Ibrahim N, Rivera E, Royce M, Cleeland CS, Hortobagyi GN (2004) Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 25(3):94–102

    Article  PubMed  CAS  Google Scholar 

  46. Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM et al (2010) Cancer and inflammation: promise for biologic therapy. J Immunother 33(4):335–351

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to acknowledge Ricardo Mottu and Katharina Alvarez for manuscript preparation. Supported by Grants R03 CA123553 (A.M.B.), Susan Komen Disparities Career Award (A.M.B), R01 CA089608 (M.L.B., P.T.), K07 CA160753 (M.P.), and CA16672 (MD Anderson Cancer Center) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

Conflict of interest

  The authors indicated no potential conflicts of interest.

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Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    James L. Murray, Suk Young Yoo, Kim-Anh Do, Mala Pande, Renke Zhou, Aysegul A. Sahin, Melissa L. Bondy & Abenaa M. Brewster

  2. The Arizona Cancer Center, Tucson, AZ, USA

    Patricia Thompson

  3. Baylor College of Medicine, Houston, TX, USA

    Renke Zhou, Yanhong Liu & Melissa L. Bondy

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  1. James L. Murray
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Correspondence to James L. Murray.

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Murray, J.L., Thompson, P., Yoo, S.Y. et al. Prognostic value of single nucleotide polymorphisms of candidate genes associated with inflammation in early stage breast cancer. Breast Cancer Res Treat 138, 917–924 (2013). https://doi.org/10.1007/s10549-013-2445-x

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