Genetic Polymorphisms of the TGFB1 Signal Peptide and Promoter Region: Role in Wilms Tumor Susceptibility?

Main Article Content

Cintya Mayumi Ishibashi
Carlos Eduardo Coral de Oliveira
Roberta Losi Guembarovski
Bruna Karina Banin Hirata
Glauco Akelinghton Freire Vitiello
Alda Losi Guembarovski
Marla Karine Amarante
Karen Brajão de Oliveira
Marina Okuyama Kishima
Carolina Batista Ariza
Maria Angelica Ehara Watanabe


genetic polymorphism, nephroblastoma, prognosis, susceptibility, TGFB1, Wilms tumor


The aim of the present study was to investigate the rs1800468 (G-800A), rs1800469 (C-509T), rs1800470 (C29T), and rs1800471 (G74C) TGFB1 genetic polymorphisms and their haplotype structures in patients with Wilms Tumor (WT) and neoplasia-free controls. The genomic DNA was extracted from 35 WT patients and 160 neoplasia-free children, and the TGFB1 polymorphisms were genotyped by polymerase chain reaction, followed by restriction fragment length polymorphism. The haplotype structures were inferred, and permutation and logistic regression tests were performed to check for differences in haplotype distribution between the control and WT individuals. Positive associations were found in the recessive model for rs1800469 T allele (OR: 8.417; 95% CI: 3.177 to 22.297; P < 0.001) and for the rs1800470 C allele (OR: 3.000; 95% CI: 1.296 to 6.944; P = 0.01). Haplotype analysis revealed a significant negative association between GCTG and WT (OR: 0.236, 95% CI: 0.105 to 0.534; P = 0.0002); by contrast, the GTTG haplotype was associated with increased risk for WT (OR: 12.0; 95% CI: 4.202 to 34.270; P < 0.001). Furthermore, rs1800469 was negatively correlated with tumor size and a trend toward a positive correlation for capsular invasion was observed in the dominant model (Tau-b: −0.43, P = 0.02 and tau-b: 0.5, P = 0.06, respectively). This is the first study with rs1800468, rs1800469, rs1800470, and rs1800471 TGFB1 polymorphisms in WT, and our results suggest that the TGFB1 promoter and signal peptide region polymorphisms may be associated with WT susceptibility and clinical presentation.

Abstract 796 | PDF Downloads 787 HTML Downloads 323 XML Downloads 108


1. Rivera MN, Haber DA. Wilms’ tumour: Connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer. 2005;5(9):699–712.
2. Akpa MM, Iglesias D, Chu L, Thiebaut A, Jentoft I, Hammond L, et al. Wilms tumor suppressor, WT1, cooperates with microRNA-26a and microRNA-101 to suppress translation of the polycomb protein, EZH2, in mesenchymal stem cells. J Biol Chem. 2016;291(8):3785–95. M115.678029
3. Royer-Pokora B. Genetics of pediatric renal tumors. Pediatr Nephrol. 2013;28(1):13–23.
4. Cunningham ME, Klug TD, Nuchtern JG, Chintagumpala MM, Venkatramani R, Lubega J, et al. Global disparities in Wilms tumor. J Surg Res. 2020;247:34–51.
5. Pritchard-Jones K. Controversies and advances in the management of Wilms’ tumour. Arch Dis Childhood. 2002;87(3):241–4.
6. Maturu P. The inflammatory microenvironment in Wilms tumors. In: van den Heuvel-Eibrink MM, editor. Wilms tumor. Brisbane; 2016.
7. Duffner PK, Cohen ME, Parker MS. Prospective intellectual testing in children with brain tumors. Ann Neurol. 1988;23(6):575–9.
8. Dome JS, Cotton CA, Perlman EJ, Breslow NE, Kalapurakal JA, Ritchey ML, et al. Treatment of anaplastic histology Wilms’ tumor: Results from the fifth national Wilms’ tumor study. J Clin Oncol. 2006;24(15):2352–8. JCO.2005.04.7852
9. Yaqub S, Aandahl EM. Inflammation versus adaptive immunity in cancer pathogenesis. Crit Rev Oncog. 2009;15(1–2):43–63.
10. Bush KT, Sakurai H, Steer DL, Leonard MO, Sampogna RV, Meyer TN, et al. TGF-beta superfamily members modulate growth, branching, shaping, and patterning of the ureteric bud. Dev Biol. 2004;266(2):285–98.
11. Fontoura BM, Blobel G, Yaseen NR. The nucleoporin Nup98 is a site for GDP/GTP exchange on ran and termination of karyopherin beta 2-mediated nuclear import. J Biol Chem. 2000;275(40):31289–96.
12. Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. TGF-beta – An excellent servant but a bad master. J Transl Med. 2012;10:183.
13. Hamatani H, Sakairi T, Ikeuchi H, Kaneko Y, Maeshima A, Nojima Y, et al. TGF-beta1 alters DNA methylation levels in promoter and enhancer regions of the WT1 gene in human podocytes. Nephrology. 2019;24(5):575–84. http://dx.doi. org/10.1111/nep.13411
14. Fanni D, Fanos V, Monga G, Gerosa C, Locci A, Nemolato S, et al. Expression of WT1 during normal human kidney development. J Matern Fetal Neonatal Med. 2011;24(Suppl 2):44–7.
15. Bandiera R, Sacco S, Vidal VP, Chaboissier MC, Schedl A. Steroidogenic organ development and homeostasis: A WT1-centric view. Mol Cell Endocrinol. 2015;408:145–55.
16. Aslan A, Erdem H, Celik MA, Sahin A, Cankaya S. Investigation of insulin-like growth factor-1 (IGF-1), P53, and Wilms’ tumor 1 (WT1) expression levels in the colon polyp sub-types in colon cancer. Med Sci Monit. 2019;25:5510–17.
17. Wang X, Gao P, Lin F, Long M, Weng Y, Ouyang Y, et al. Wilms’ tumour suppressor gene 1 (WT1) is involved in the carcinogenesis of lung cancer through interaction with PI3K/ Akt pathway. Cancer Cell Int. 2013;13(1):114.
18. Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F, et al. Quantitative assessment of WT1 expression by real-time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia. 2002;16(10):2115–21.
19. Sakaguchi AY, Amarante MK, Oliveira CECd, Hiroki CH, Trigo FC, Watanabe MAE. Transforming growth factor-beta 1: Possible involvement with acute lymphoblastic leukemia prognosis in pediatric patients. Clin Oncol Res. 2020;6.
20. Parsons LN. Wilms tumor: Challenges and newcomers in prognosis. Surg Pathol Clin. 2020;13(4):683–93.
21. Martelossi Cebinelli GC, Paiva Trugilo K, Badaro Garcia S, Brajao de Oliveira K. TGF-beta1 functional polymorphisms: A review. Eur Cytokine Netw. 2016;27(4):81–9.
22. Choi YJ, Kim N, Shin A, Lee HS, Nam RH, Chang H, et al. Influence of TGFB1 C-509T polymorphism on gastric cancer risk associated with TGF-beta1 expression in the gastric mucosa. Gastric Cancer. 2015;18(3):526–37.
23. Jin G, Deng Y, Miao R, Hu Z, Zhou Y, Tan Y, et al. TGFB1 and TGFBR2 functional polymorphisms and risk of esophageal squamous cell carcinoma: A case-control analysis in a Chinese population. J Cancer Res Clin Oncol. 2008;134(3):345–51.
24. Vitiello GAF, Guembarovski RL, Hirata BKB, Amarante MK, de Oliveira CEC, de Oliveira KB, et al. Transforming growth factor beta 1 (TGFβ1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis. J Cancer Res Clin Oncol. 2018;144(4):645–55. s00432-018-2585-9
25. Shin A. Genetic polymorphisms of the transforming growth factor-1 gene and breast cancer risk: A possible dual role at different cancer stages. Cancer Epidemiol Biomark Prevent. 2005;14(6):1567– 70.
26. Aidar M, Line SR. A simple and cost-effective proto-col for DNA isolation from buccal epithelial cells. Braz Dent  J. 2007;18(2):148–52.
27. Jin Q, Hemminki K, Grzybowska E, Klaes R, Soderberg M, Zientek H, et al. Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers. Int J Cancer. 2004;112(1):94–9.
28. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68(4):978–89.
29. Hohenstein P, Pritchard-Jones K, Charlton J. The yin and yang of kidney development and Wilms’ tumors. Genes Dev. 2015;29(5):467–82.
30. Amarante MK, de Oliveira CEC, Ariza CB, Sakaguchi AY, Ishibashi CM, Watanabe MAE. The predictive value of transforming growth factor-β in Wilms tumor immunopathogenesis. Int Rev Immunol. 2017;36(4):233–9.
31. Javle M, Li Y, Tan D, Dong X, Chang P, Kar S, et al. Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PLoS One. 2014;9(1):e85942.
32. Zhang L, Liu W, Qin Y, Wu R. Expression of TGF-beta1 in Wilms’ tumor was associated with invasiveness and disease progression. J Pediatr Urol. 2014;10(5):962–8.
33. Lu J, Tao Y-F, Li Z-H, Cao L, Hu S-Y, Wang N-N, et al. Analyzing the gene expression profile of anaplastic histology Wilms’ tumor with real-time polymerase chain reaction arrays. Cancer Cell Int. 2015;15(1).
34. Parvizi S, Mohammadzadeh G, Karimi M, Noorbehbahani M, Jafary A. Effects of two common promoter polymorphisms of transforming growth factor-beta1 on breast cancer risks in Ahvaz, West South of Iran. Iranian J Cancer Prev. 2016;9(1):e5266.
35. Ramos-Flores C, Romero-Gutierrez T, Delgado-Enciso  I, Maldonado GE, Plascencia VM, Vazquez-Vuelvas OF, et al. Polymorphisms in the genes related to angiogenesis are associated with uterine cervical cancer. Int J Gynecol Cancer. 2013;23(7):1198–204. IGC.0b013e31829f4c6f
36. Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew  S, Vallone J, et al. Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med. 2004;169(2):214–19.
37. Dunning AM, Ellis PD, McBride S, Kirschenlohr HL, Healey CS, Kemp PR, et al. A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res. 2003;63(10):2610–15.
38. Berndt SI, Huang WY, Chatterjee N, Yeager M, Welch R, Chanock SJ, et al. Transforming growth factor beta 1 (TGFB1) gene polymorphisms and risk of advanced colorectal adenoma. Carcinogenesis. 2007;28(9):1965–70.
39. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, et al. Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet. 1999;8(1):93–7.
40. 40. Susianti H, Handono K, Purnomo BB, Widodo N, Gunawan A, Kalim H. Changes to signal peptide and the level of transforming growth factor-beta1 due to T869C polymorphism of TGF beta1 associated with lupus renal fibrosis. SpringerPlus. 2014;3:514.
41. Hastie ND. Wilms’ tumour 1 (WT1) in development, homeo-stasis and disease. Development. 2017;144(16):2862–72.
42. Yang L, Han Y, Saurez Saiz F, Minden MD. A tumor suppressor and oncogene: The WT1 story. Leukemia. 2007;21(5):868– 76.
43. Gautam KA, Pooja S, Sankhwar SN, Sankhwar PL, Goel A, Rajender S. c.29C>T polymorphism in the transforming growth factor-beta1 (TGFB1) gene correlates with increased risk of urinary bladder cancer. Cytokine. 2015;75(2):344–8.
44. Shi Q, Wu H, Li Y, Shen L, Tian X, Lin T, et al. Inhibition of Wilms’ tumor proliferation and invasion by blocking TGF-beta receptor I in the TGF-beta/Smad signaling pathway. BioMed Res Int. 2020;2020:8039840.