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Association between HER2 and IL-6 genes polymorphisms and clinicopathological characteristics of breast cancer: significant role of genetic variability in specific breast cancer subtype

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Abstract

Clinical implications of single nucleotide polymorphisms (SNPs) in breast cancer have been explored to determine the impact of SNP in modulating the pathogenesis of breast cancer. This study aimed to evaluate the association between HER2 (rs2517956) and (IL-6) (rs1800795 and rs2069837) and clinicopathological characteristics in HER2-positive and HER2-negative breast cancer in Tunisian women. A retrospective cohort study included 273 patients. Genomic DNA was extracted from peripheral blood samples, and genotyping of selected SNP was performed by PCR–RFLP assays. Statistical analysis was then carried out to assess genotypic frequencies and genetic association in relation to breast cancer subtypes. SHEsis software was applied to IL-6 haplotypic structure analysis. The distribution of genotype frequencies of rs2517956, rs1800795 and rs2069837 showed no statistically difference between HER2-positive and HER2-negative breast cancer. HER2 (rs2517956) was associated with tumor size (p = 0.01) and age at diagnosis (p = 0.02) in HER2-negative breast cancers, but no significant association was observed in HER2-positive breast cancer. For IL-6 gene, none of the clinicopathological parameters were associated with rs1800795 and rs2069837 in both breast cancer subtypes (p > 0.05). SHEsis analysis revealed a high linkage disequilibrium between rs1800795 and rs2069837; differences in the distribution of IL-6 two loci haplotypes were statistically negative between HER2-positive and HER2-negative breast cancer (p = 0.20) which confirmed no association with HER2 overexpression. This study demonstrates that rs2517956 is associated with clinicopathological characteristics in HER2-negative breast cancer, which could have a differential prognostic role compared to HER2-positive breast cancer.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Tunisia: Globocan 2018. In: Global cancer observatory (2019). http://gco.iarc.fr/today/data/factsheets/populations/788-tunisia-fact-sheets.pdf. Accessed 24 Dec 2019.

  3. Bannour I, Briki R, Zrairi F, et al. Cancer du sein au grand Maghreb: epidemiologie et stratégies de lutte. Revue de la littérature. Tunis Med. 2018;96:658–64.

    PubMed  Google Scholar 

  4. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2(HER2) in cancers: overexpression and therapeutic implications. Mol Bio Int. 2014;2014:852748.

    Google Scholar 

  5. Liu Q, Kulak MV, Borcherding N, et al. A novel HER2 gene body enhancer contributes to HER2 expression. Oncogene. 2014;37:687–94.

    Google Scholar 

  6. Zare S, Rong J, Daehne S, et al. Implementation of the 2018 American Society of Clinical Oncology/College of American Pathologists Guidelines on HER2/neu Assessment by FISH in breast cancers: predicted impact in a single institutional cohort. Mod Pathol. 2019;32:1566–73.

    PubMed  Google Scholar 

  7. Shah D, Osipo C. Cancer stem cells and HER2 positive breast cancer: the story so far. Genes Dis. 2016;3:114–23.

    PubMed  PubMed Central  Google Scholar 

  8. Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W. Human breast cancer: correlation of relapse and survival with amplification of the HER–2/neu oncogene. Science. 1987;235:177–82.

    CAS  PubMed  Google Scholar 

  9. Chung SS, Giehl N, Wu Y, Vadgama JV. STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits. Int J Oncol. 2014;44:403–11.

    CAS  PubMed  Google Scholar 

  10. Furrer D, Lemieux J, Côté MA, et al. Evaluation of human epidermal growth factor receptor 2(HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors. Breast. 2016;30:191–6.

    PubMed  Google Scholar 

  11. Singla H, Kalra S, Kheterpal P, Kumar V, Munshi A. Role of genomic alterations in HER2 positive breast carcinoma: focus on susceptibility and trastuzumab-therapy. Curr Cancer Drug Targets. 2017;17:344–56.

    CAS  PubMed  Google Scholar 

  12. Ferrari A, Vincent-Salomon A, Pivot X, et al. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers. Nat Commun. 2016;17:12222.

    Google Scholar 

  13. Sağlam Ö, Ünal ZS, Subaşı C, Ulukaya E, Karaöz E. IL-6 orginated from breast cancer tissue-derived mesenchymal stromal cells may contribute to carcinogenesis. Tumor Biol. 2015;36:5667–77.

    Google Scholar 

  14. Agnoli C, Grioni S, Pala V, et al. Biomarkers of inflammation and breast cancer risk: a case-control study nested in the EPIC-Varese cohort. Sci Rep. 2017;7:12708.

    PubMed  PubMed Central  Google Scholar 

  15. Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res. 1999;19:1427–32.

    CAS  PubMed  Google Scholar 

  16. Yu K, Di G-H, Fan L, Chen A-X, Yang C, Shao Z-M. Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25,703 subjects. Breast Cancer Res Treat. 2012;122:483–8.

    Google Scholar 

  17. Milovanović J, Todorović-Raković N, Radulovic M. Interleukin-6 and interleukin-8 serum levels in prognosis of hormone-dependent breast cancer. Cytokine. 2019;118:93–8.

    PubMed  Google Scholar 

  18. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    CAS  PubMed  Google Scholar 

  19. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Liou S, Lee JS, Jie C, et al. HER2 overexpression triggers an IL1α proinflammatory circuit to drive tumorigenesis and promote chemotherapy resistance. Cancer Res. 2018;78:2010–51.

    Google Scholar 

  21. Shi TY, Zhu ML, He J, et al. Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women. Hum Genet. 2013;132:301–12.

    CAS  PubMed  Google Scholar 

  22. Zheng X, Han C, Shan R, et al. Association of interleukin-6 polymorphisms with susceptibility to hepatocellular carcinoma. Int J Clin Exp Med. 2015;8:6252–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ruzzo A, Catalano V, Canestrari E, et al. Genetic modulation of the interleukin 6 (IL-6) system in patients with advanced gastric cancer: a background for an alternative target therapy. BMC Cancer. 2014;14:357.

    PubMed  PubMed Central  Google Scholar 

  24. Li H, Dai H, Li H, Li B, Shao Y. Polymorphisms of the highly expressed IL-6 gene in the papillary thyroid cancer susceptibility among Chinese. Curr Mol Med. 2019;19:443–51.

    CAS  PubMed  Google Scholar 

  25. Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer. 2003;103:642–7.

    CAS  PubMed  Google Scholar 

  26. DeMichele A, Martin A-M, Mick R, et al. Interleukin-6 174G-C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res. 2003;63:8051–6.

    CAS  PubMed  Google Scholar 

  27. Noman AS, Uddin M, Chowdhury AA, et al. Serum sonic hedgehog (SHH) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer. Sci Rep. 2017;7:1796.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. de Bruin MA, Ford JM, Kurian AW. Genetic polymorphisms as predictors of breast cancer risk. Curr Breast Cancer Rep. 2012;4:232–9.

    CAS  Google Scholar 

  29. Abbad A, Baba H, Dehbi H, et al. Genetics of breast cancer in African populations: a literature review. Glob Health Epidmiol Genom. 2018;3:e8.

    CAS  Google Scholar 

  30. Han W, Kang D, Lee JE, et al. A haplotype analysis of HER-2 gene polymorphisms: association with breast cancer risk, HER-2 protein expression in the tumor, and disease recurrence in Korea. Clin Cancer Res. 2005;11:4775–8.

    CAS  PubMed  Google Scholar 

  31. Pu X, Gu Z, Wang X. Polymorphisms of the interleukin 6 gene and additional gene-gene interaction contribute to cervical cancer susceptibility in Eastern Chinese women. Arch Gynecol Obstet. 2016;294:1305–10.

    CAS  PubMed  Google Scholar 

  32. Rebbeck TR, Walker AH, Phelan CM, et al. Defining etiologic heterogeneity in breast cancer using genetic biomarkers. Prog Clin Biol Res. 1997;396:53–61.

    CAS  PubMed  Google Scholar 

  33. Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Chouchane L. Genetic variation in pro-inflammatory cytokines (interleukin-1beta, interleukin-1alpha and interleukin-6) associated with the aggressive forms, survival, and relapse prediction of breast carcinoma. Eur Cytokine Netw. 2005;16:253–60.

    CAS  PubMed  Google Scholar 

  34. Madrid-Paredes A, Cañadas-Garre M, Sánchez-Pozo A, et al. ABCB1 C3435T gene polymorphism as a potential biomarker of clinical outcomes in HER2-positive breast cancer patients. Pharmacol Res. 2016;108:111–8.

    CAS  PubMed  Google Scholar 

  35. Abana CO, Bingham BS, Cho JH, et al. IL-6 variant is associated with metastasis in breast cancer patients. PLoS ONE. 2017;12:e0181725.

    PubMed  PubMed Central  Google Scholar 

  36. Su Y, Jilang Y, Sun S, et al. Effects of HER2 genetic polymorphisms on its protein expression in breast cancer. Cancer Epidemiol. 2015;39:1123–7.

    PubMed  Google Scholar 

  37. Peng X, Shi J, Sun W, et al. Genetic polymorphisms of IL-6 promoter in cancer susceptibility and prognosis: a meta-analysis. Oncotarget. 2018;9:12351–64.

    PubMed  PubMed Central  Google Scholar 

  38. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Matsusaka S, Hanna DL, Cao S, et al. Prognostic impact of IL-6 genetic variants in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. Clin Cancer Res. 2016;22:3218–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Madeleine MM, Johnson LG, Malkki M, et al. Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer. Breast Cancer Res Treat. 2011;129:887–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.

    PubMed  Google Scholar 

  42. Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res. 1988;16:1215.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15:97–8.

    CAS  PubMed  Google Scholar 

  44. Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7:e1000279.

    PubMed  PubMed Central  Google Scholar 

  45. Cresti N, Lee J, Rourke E, et al. Genetic variants in the HER2 gene: influence on HER2 overexpression and loss of heterozygosity in breast cancer. Eur J Cancer. 2016;55:27–37.

    CAS  PubMed  Google Scholar 

  46. Si P, Xu Y, Ouyang T, Li J, Wang T, Fan Z. HER2 Pro1170Ala polymorphism is associated with decreased survival rate in HER2-negative breast cancer. Oncol Lett. 2017;13:3793–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Broeks A, Schmidt MK, Sherman ME, et al. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet. 2011;20:3289–303.

    PubMed  PubMed Central  Google Scholar 

  48. Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551:92–4.

    PubMed  PubMed Central  Google Scholar 

  49. Avalos-Navarro G, Muñoz-Valle JF, Daneri-Navarro A, et al. Circulating soluble levels of MIF in women with breast cancer in the molecular subtypes: relationship with Th17 cytokine profile. Clin Exp Med. 2019;19:385–91.

    CAS  PubMed  Google Scholar 

  50. Haritos C, Michaelidou K, Mavridis K, et al. Kallikrein-related peptidase 6 (KLK6) expression differentiates tumor subtypes and predicts clinical outcome in breast cancer patients. Clin Exp Med. 2018;18:203–13.

    CAS  PubMed  Google Scholar 

  51. Chérel M, Campion L, Bézieau S, et al. Molecular screening of interleukin-6 gene promoter and influence of −174G/C polymorphism on breast cancer. Cytokine. 2009;47:214–23.

    PubMed  Google Scholar 

  52. DeMichele A, Gray R, Horn M, et al. Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer. Cancer Res. 2009;69:4184–91.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all the medical staff and medical assistants for their help in collecting biological samples and reviewing medical data. We are grateful to Dr. Sana Sfar (Assistant professor, Faculty of Pharmacy of Monastir) and Dr. Karim Farhat for their assistance in haplotype analysis, and Dr. Ridha M’rad, head of department of congenital and hereditary diseases (Charles Nicolle Hospital, Tunis) for his support and advices. We thank Mrs. Asma Ben Youssef, Provision Lab’ solutions Company for technical support and Dr. Afef Slimani for her experimental assistance. The author thanks also Dr. Ines Jelassi.

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Authors and Affiliations

  1. Research Laboratory “Environment, Inflammation, Signaling and Pathologies” (LR18ES40), Faculty of Medicine of Monastir, University of Monastir, Monastir, Tunisia

    Om Elez Bouhniz, Sonia Zaied & Abderraouf Kenani

  2. Department of Clinical Oncology, CHU Fattouma Bourguiba, Monastir, Tunisia

    Sonia Zaied

  3. Department of Surgical Oncology, Salah Azaiez Institute, Tunis, Tunisia

    Lamia Naija & Khaled Rahal

  4. Department of Immuno-Histo-Cytology, Salah Azaiez Institute, Tunis, Tunisia

    Ilhem Bettaieb & Maha Driss

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  1. Om Elez Bouhniz
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Correspondence to Om Elez Bouhniz.

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All procedures performed in this study were in accordance with the ethical standards of the institutional ethics committee of Salah Azaiez of Tunis (ISA/2018/16) and research ethics committee of Faculty of Medicine of Monastir (IORG 0009738 No 31/OMB 0990-0279) and with the 1964 Helsinki declaration and its later amendments.

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Bouhniz, O.E., Zaied, S., Naija, L. et al. Association between HER2 and IL-6 genes polymorphisms and clinicopathological characteristics of breast cancer: significant role of genetic variability in specific breast cancer subtype. Clin Exp Med 20, 427–436 (2020). https://doi.org/10.1007/s10238-020-00632-5

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  • DOI: https://doi.org/10.1007/s10238-020-00632-5

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