The Investigation of WRAP53 rs2287499 Association with Thyroid Cancer Risk and Prognosis among the Azeri Population in Northwest Iran

Document Type: Original Article


1 Department of Biological Sciences, Faculty of Natural Siences, Ahar Branch, Islamic Azad University, Ahar-Iran

2 Department of Biology, Faculty of Natural Sciences, Tabriz University, Tabriz-Iran

3 Professor, Department of Animal Biology, Faculty of Natural Sciences, Tabriz University, Tabriz, Iran

4 Assistant Professor, Department of Cellular and Molecular Biology, Faculty of Science, Azarbaijan Shahid Madani University, Tabriz-Iran

5 Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran


Background: TP53 and the oncogene WRAP53 are adjoining genes, producing p53-WRAP53α sense-antisense RNA couples. WRAP53α is indispensable for p53 mRNA regulation and p53 induction following DNA damage. Up-regulated WRAP53β can induce neoplastic transformation and cancer cell survival. All these, along with the associations of WRAP53 single nucleotide polymorphisms with tumor incidence and prognosis, highlighted an impact in human cancers. Considering the importance of WRAP53 in modulating p53, and the frequent occurrence of thyroid cancer, we examined the association of a WRAP53 SNP (rs2287499) with thyroid cancer risk and prognosis among Iranian-Azeri population.
Methods: This research was done in Tabriz-IRAN in 2014. DNA samples obtained from 106 patients and 196 controls were subjected to polymerase chain-reaction-based single-strand conformational polymorphism (PCR-SSCP) analysis. Genotypes were characterized by sequencing. Correlations of desired SNP with thyroid cancer as well as age, gender, involved thyroid lobe, lymph node metastasis, tumor type, stage, and size were estimated using Chi-square (χ2) or Fisher's exact tests with a P-value less than 0.05 as significant.
Results: rs2287499 is not associated with thyroid cancer predisposition. Except for gender, none of the clinicopathologic factors were significantly linked to the examined genotypes.
Conclusions: rs2287499 is not a genetic risk factor for thyroid cancer. Although rs2287499 is not assessable as a biomarker to predict prognosis based on clinicopathologic parameters, the considerable association with gender suggests that this SNP may indirectly be relevant to gender-associated disease manifestation. Further investigations on distinct types of thyroid tumors are needed to fully characterize the rs2287499 status in thyroid malignancies.


  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer 2015; 136(5):E359-E86.
  2. Khayamzadeh M, Khayamzadeh M, Tadayon N, Salmanian R, Zham H, Razzaghi Z, et al. Survival of Thyroid Cancer and Social Determinants in Iran. Asian Pac J Cancer Prev 2011; 12:95-8.
  3. Farzadfar F, Peykari N, Larijani B, Rahimzadeh S, Rezaei-Darzi E, Saeedi Moghaddam S. A comprehensive study on national and sub national trend in thyroid cancer prenalence in the iranian populayion, 1990–2010. Iranian Journal of Diabetes and Metabolism 2016; 15(2):91-100.
  4. Nix P, Nicolaides A, Coatesworth A. Thyroid cancer review 3: management of medullary and undifferentiated thyroid cancer. International journal of clinical practice 2006; 60(1):80-4.
  5. Katoh H, Yamashita K, Enomoto T, Watanabe M. Classification and general considerations of thyroid cancer. Ann Clin Pathol 2015; 3(1):1045.
  6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians. 2016; 66(1):7-30.
  7. Fard-Esfahani P, Fard-Esfahani A, Saidi P, Fayaz S, Mohabati R, Majdi M. An increased risk of differentiated thyroid carcinoma in Iran with the 677C→ T homozygous polymorphism in the MTHFR Gene. Cancer epidemiology 2011; 35(1):56-8.
  8. Legakis I, Syrigos K. Recent advances in molecular diagnosis of thyroid cancer. Journal of thyroid research 2011; 2011.
  9. Kim SK, Park HJ, Hong IK, Chung J-H, Eun YG. A missense polymorphism (rs11466653, Met326Thr) of toll-like receptor 10 (TLR10) is associated with tumor size of papillary thyroid carcinoma in the Korean population. Endocrine 2013; 43(1):161-9.
  10. Wang Y-L, Feng S-H, Guo S-C, Wei W-J, Li D-S, Wang Y, et al. Confirmation of papillary thyroid cancer susceptibility loci identified by genome-wide association studies of chromosomes 14q13, 9q22, 2q35 and 8p12 in a Chinese population. Journal of medical genetics. 2013:jmedgenet-2013-101687.
  11. Yan Y, Han F, Fu H, Xia W, Qin X. Association between MTHFR C677T polymorphism and thyroid cancer risk: a meta-analysis. Tumor Biology 2014; 35(8):7707-12.
  12. Dehghan R, Feizi MAH, Pouladi N, Adampourezare M, Farajzadeh D. The TP53 intron 6 G13964C Polymorphism and Risk of Thyroid and Breast Cancer Development in the Iranian Azeri Population. Asian Pacific Journal of Cancer Prevention 2015; 16(7):3073-7.
  13. Farnebo M, Bykov VJ, Wiman KG. The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. Biochemical and biophysical research communications 2010; 396(1):85-9.
  14. Pelechano V, Steinmetz LM. Gene regulation by antisense transcription. Nature Reviews Genetics 2013; 14(12):880-93.
  15. Brophy JA, Voigt CA. Antisense transcription as a tool to tune gene expression. Molecular systems biology 2016; 12(1):854.
  16. Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman KG, Farnebo M. Wrap53, a Natural p53 Antisense Transcript Required for p53 Induction upon DNA Damage. Molecular Cell 2016; 64(5):1009.
  17. Farnebo M. Wrap53, a novel regulator of p53. Cell Cycle 2009; 8(15):2343-6.
  18. Mahmoudi S, Henriksson S, Farnebo L, Roberg K, Farnebo M. WRAP53 promotes cancer cell survival and is a potential target for cancer therapy. Cell death & disease 2011; 2(1):e114.
  19. Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM, Veenstra TD, et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 2009; 323(5914):644-8.
  20. Hiyama K, Hiyama E, Tanimoto K, Nishiyama M. Role of telomeres and telomerase in cancer. Telomeres and Telomerase in Cancer: Springer 2009; P 171-80.
  21. Rao X, Huang D, Sui X, Liu G, Song X, Xie J, et al. Overexpression of WRAP53 is associated with development and progression of esophageal squamous cell carcinoma. PloS one 2014; 9(3):e91670.
  22. Velázquez-Fernández D, Laurell C, Saqui-Salces M, Pantoja JP, Candanedo-Gonzalez F, Reza-Albarrán A, et al. Differential RNA expression profile by cDNA microarray in sporadic primary hyperparathyroidism (pHPT): primary parathyroid hyperplasia versus adenoma. World journal of surgery 2006; 30(5):705-13.
  23. Zhang Y, Eberhard DA, Frantz GD, Dowd P, Wu TD, Zhou Y, et al. GEPIS—quantitative gene expression profiling in normal and cancer tissues. Bioinformatics 2004; 20(15):2390-8.
  24. Zhang H, Wang D-W, Adell G, Sun X-F. WRAP53 is an independent prognostic factor in rectal cancer-a study of Swedish clinical trial of preoperative radiotherapy in rectal cancer patients. BMC cancer 2012; 12(1):294.
  25. Mędrek K, Magnowski P, Masojć B, Chudecka-Głaz A, Torbe B, Menkiszak J, et al. Association of common WRAP 53 variant with ovarian cancer risk in the Polish population. Molecular biology reports 2013; 40(3):2145-7.
  26. Schildkraut JM, Goode EL, Clyde MA, Iversen ES, Moorman PG, Berchuck A, et al. Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer. Cancer research 2009; 69(6):2349-57.
  27. Garcia‐Closas M, Kristensen V, Langerød A, Qi Y, Yeager M, Burdett L, et al. Common genetic variation in TP53 and its flanking genes, WDR79 and ATP1B2, and susceptibility to breast cancer. International journal of cancer 2007; 121(11):2532-8.
  28. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Annals of surgical oncology 2010; 17(6):1471-4.
  29. Demeke T, Jenkins GR. Influence of DNA extraction methods, PCR inhibitors and quantification methods on real-time PCR assay of biotechnology-derived traits. Analytical and bioanalytical chemistry 2010; 396(6):1977-90.
  30. Garritano S, Gemignani F, Voegele C, Nguyen-Dumont T, Le Calvez-Kelm F, De Silva D, et al. Determining the effectiveness of High Resolution Melting analysis for SNP genotyping and mutation scanning at the TP53 locus. BMC genetics 2009; 10(1):5.
  31. Konstantinos KV, Panagiotis P, Antonios VT, Agelos P, Argiris NV. PCR–SSCP: A method for the molecular analysis of genetic diseases. Molecular biotechnology 2008; 38(2):155-63.
  32. Green M, Sambrook J, Sambrook J. Molecular cloning: a laboratory manual 4 edition Cold Spring Harbor Laboratory Press. New York. 2012.
  33. Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. American journal of epidemiology 2009; 169(4):505-14.
  34. Malaguarnera R, Vella V, Vigneri R, Frasca F. p53 family proteins in thyroid cancer. Endocrine-Related Cancer. 2007;14(1):43-60.
  35. Morita N, Ikeda Y, Takami H. Clinical significance of p53 protein expression in papillary thyroid carcinoma. World journal of surgery 2008; 32(12):2617.
  36. Marcello MA, Morari EC, Cunha LL, De Nadai Silva AC, Carraro DM, Carvalho AL, et al. P53 and expression of immunological markers may identify early stage thyroid tumors. Clinical and Developmental Immunology. 2013; 2013.
  37. Bachmann K, Pawliska D, Kaifi J, Schurr P, Zoerb J, Mann O, et al. P53 is an independent prognostic factor for survival in thyroid cancer. Anticancer research 2007; 27(6B):3993-7.
  38. Joerger AC, Fersht AR. The p53 pathway: Origins, inactivation in cancer, and emerging therapeutic approaches. Annual review of biochemistry 2016; 85:375-404.
  39. Vousden KH, Prives C. P53 and prognosis: new insights and further complexity. Cell 2005; 120(1):7-10.
  40. Levine A, Hu W, Feng Z. The P53 pathway: what questions remain to be explored? Cell Death & Differentiation. 2006; 13(6):1027-36.
  41. Bonab AS, Pouladi N, Hosseinpourfeizi MA, Gavgani RR, Dehghan R, Azarfam P, et al. Single-strand conformational polymorphism analysis of a common single nucleotide variation in WRAP53 gene, rs2287499, and evaluating its association in relation to breast cancer risk and prognosis among Iranian-Azeri population. Medical Oncology 2014; 31(9):1-7.
  42. Safavi A, Azizi F, Jafari R, Chaibakhsh S, Safavi AA. Thyroid Cancer Epidemiology in Iran: a Time Trend Study. Asian Pacific journal of cancer prevention: APJCP. 2016; 17(1):407-12.