Environmental Science and Pollution Research

, Volume 25, Issue 22, pp 21535–21542 | Cite as

Genetic aberrations of the K-ras proto-oncogene in bladder cancer in relation to pesticide exposure

  • Diaa A. Hameed
  • Heba A. Yassa
  • Michael N. Agban
  • Randa T. Hanna
  • Ahmed M. Elderwy
  • Mohamed A. Zwaita
Research Article


In Egypt, bladder cancer is one of the most popular cancers, accounting for 31% of all cancer cases. It ranks first in males about 16.2% of male cancer. The incidence in rural areas among males is near 32 per 100,000. The exact etiology of bladder cancer is still unknown; K-ras gene is known as a critical DNA target for chemical carcinogens such as pesticide. Some occupational hazard exposure is thought to be directly genotoxic, while others might enhance the mutagenicity and carcinogenicity of directly acting genotoxic agents. Analysis of the relationship between pesticide exposure and mutation in the K-ras gene in human bladder cancer. One hundred patients were diagnosed with bladder cancer and two hundred controls attended the outpatient clinic; after taking consent and filling a questionnaire for age, sex, occupation and pesticide exposure, surgically resected specimens were collected and the samples were used to determine the k-ras mutation. Blood samples were taken to analyze the level of acetylcholinesterase enzyme and level of P53. The present study indicated that pesticide exposure may play a great role in malignant transformation of the bladder cells through mutation in the K-ras gene; there was a significant correlation between the acetylcholinesterase enzyme level and k-ras mutation (p < 0.001). The results revealed that the level of P53 was significantly high in comparison with the control group (p < 0.001). These findings give an alarm to decrease the amount of pesticides used in our area; also, p53 may be used as an indicator to bladder cancer.


Bladder cancer Acetylcholinesterase K-ras Mutation 



Special thanks to the research funding unit, Faculty of Medicine, Assiut University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdollahi M, Mostafalou S, Pournourmohammadi S, Shadnia S (2004) Oxidative stress and cholinesterase inhibition in saliva and plasma of rats following subchronic exposure to malathion. Comp Biochem Physiol C Toxicol Pharmacol 2004(137):29–34CrossRefGoogle Scholar
  2. Ahrendt SA, Decker PA, Alawi EA, Zhu Yr YR, Sanchez-Cespedes M, Yang SC, Haasler GB, Kajdacsy-Balla A, Demeure MJ, Sidransky D (2001) Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 15 92(6):1525–1530CrossRefGoogle Scholar
  3. Alguacil J, Porta M, Malats N, Kauppinen T, Kogevinas M, Benavides FG, Partanen T, Carrato A, PANKRAS II Study Group (2002) Occupational exposure to organic solvents and K-ras mutations in exocrine pancreatic cancer. Carcinogenesis 23(1):101–106CrossRefGoogle Scholar
  4. Amal SI, and El-Sebai I (1983) Epidemiology of bladder cancer and ligand binding. Volume 1. Cancer bladder, Inc Florida Press; 28–32Google Scholar
  5. American cancer society (2006) Detailed guide: bladder cancerGoogle Scholar
  6. Amr M (1999) Pesticide monitoring and its health problems in Egypt, a Third World country. Toxicology LettersVolume 107, Issues 1-3, 30 June 1999, Pages 1–13
  7. Barbacid M (1990) Ras oncogenes: their role in neoplasia. Eur J Clin Investig 20(3):225–235CrossRefGoogle Scholar
  8. Cabello G, Valenzuela M, Vilaxa A, Durán V, Rudolph I, Hrepic N, Calaf G (2001) A rat mammary tumor model induced by the organophosphorous pesticides parathion and malathion, possibly through acetylcholinesterase inhibition. Environ Health Perspect 109:471–479CrossRefGoogle Scholar
  9. Calaf G, Echiburu Chau C, Roy (2009) Organophosphorous pesticides and estrogen induce transformation of breast cells affecting p53 and c-Ha-ras genes. Int J Oncol 35:1061–1068CrossRefGoogle Scholar
  10. Callahan R (1992) p53 mutations, another breast cancer prognostic factor. J Natl Cancer Inst 84:826–827CrossRefGoogle Scholar
  11. Cattan N, Saison-Behmoaras T, Mari B, Mazeau C, Amiel JL, Rossi B, Gioanni J (2000) Screening of human bladder carcinomas for the presence of Ha-ras codon 12 mutation. Oncol Rep 7:497–500Google Scholar
  12. Du J, Wang SH, Yang Q, Chen QQ, Yao X (2016) p53 status correlates with the risk of progression in stage T1 bladder cancer: a meta-analysis. World J Surg Oncol 2016 14(1):137. CrossRefGoogle Scholar
  13. Freeman LE, Rusiecki JA, Hoppin JA, Lubin JH, Koutros S, Andreotti G, Zahm SH, Hines CJ, Coble JB, Barone-Adesi F, Sloan J, Sandler DP, Blair A, Alavanja MC (2011) Atrazine and cancer incidence among pesticide applicators in the agricultural health study (1994-2007). Environ Health Perspect 119(9):1253–1259. CrossRefGoogle Scholar
  14. Galloway T, Handy R (2003) Immunotoxicity of organophosphorous pesticides. Ecotoxicology 12:345–363CrossRefGoogle Scholar
  15. Hunter D (1989) Pesticides: a bumper year ahead. Chem. Week Feb. 8, p. 7Google Scholar
  16. Jebar AH, Hurst CD, Tomlinson DC, Johnston C, Taylor CF, Knowles MA (2005) FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 24:5218–5225CrossRefGoogle Scholar
  17. John S, Kale M, Rathore N, Bhatnagar D (2001) Protective effect of vitamin E in dimethoate and malathion induced oxidative stress in rat erythrocytes. J Nutr Biochem 12:500–504CrossRefGoogle Scholar
  18. Karachaliou N, Mayo C, Costa C, Magrí I, Gimenez-Capitan A, Molina-Vila MA, Rosell R (2013) KRAS mutations in lung cancer. Clin Lung Cancer 14(3):205–214. Epub 2012 Nov 1CrossRefGoogle Scholar
  19. Karimianpour N, Mousavi-Shafaei P, Ziaee A, Taghi M, Pourmand G, Abedi A, Ahmadi A, Alavi H (2008) Mutations of RAS gene family in specimens of bladder Cancer. Urol J 5(4):237–242Google Scholar
  20. Khaled HM (2005) Systemic management of bladder cancer in Egypt: revisited; as well as: Expert OpinInvestig Drugs. J Egypt NatlCancInst 17(3):127–131Google Scholar
  21. Knedel M, and Kin R. (1967): Butyryl cholinesterase 45:325Google Scholar
  22. Koutros S, Silverman DT, Alavanja MC, Andreotti G, Lerro CC, Heltshe S, Lynch CF, Sandler DP,Blair A, Beane Freeman LE. (2015) Occupational exposure to pesticides and bladder cancer risk. Int J Epidemiol. pii: dyv195. [ bladder _cancer _44. asp]
  23. LaRue H, Simoneau M, Fradet Y (1995) Human papilloma virus in transitional cell carcinoma of the urinary bladder. Clin Cancer Res 1:435–438Google Scholar
  24. Lee WJ, Blair A, Hoppin JA, Lubin JH, Rusiecki JA, Sandler DP, Dosemeci M, Alavanja MC (2004) Cancer incidence among pesticide applicators exposed to chlorpyrifos in the agricultural health study. J Natl Cancer Inst 96(23):1781–1789CrossRefGoogle Scholar
  25. Levine AJ, Momand J, Finlay CA (1991) The p53 tumor suppressor gene. Nature 351:453–456CrossRefGoogle Scholar
  26. Li J, Wang S, Su ZF, Yuan Y (2016) Synergistic effects of sorafenib in combination with gemcitabine or pemetrexed in lung cancer cell lines with K-ras mutations. Contemp Oncol (Pozn) 20(1):33–38. Epub 2016 Mar 16Google Scholar
  27. Mensing TT, Speijers GJ, Meulenbelt J (2003) Health implications of exposure to environmental nitrogenous compounds. Toxicol Rev 22(1):41–51CrossRefGoogle Scholar
  28. Menozzi P, Shi M, Lougarre A, Tang Z, Fournier D (2004) Mutations of acetylcholinesterase which confer insecticide resistance in Drosophila melanogaster populations. BMC Evol Biol 4:4CrossRefGoogle Scholar
  29. Noaishi M, Afify M, Mahmoud N (2011) Mutation analysis of K-ras gene in peripheral blood lymphocytes of Egyptian workers occupationally exposed to multiple pesticides. J Am Sci 7(12):1025–1030Google Scholar
  30. Nanda M, Sameer A, Syeed N, Shah Z, Murtaza I, Siddiqi M, and Ali A (2010) Genetic aberrations of the K-ras proto-oncogene in bladder cancer in Kashmiri population. Urology Journal Vol 7 No 3 SummerGoogle Scholar
  31. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P et al (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342(6250):705–708CrossRefGoogle Scholar
  32. Przybojewska B, Jagiello A, Jalmuzna P (2000) H-RAS, K-RAS, and N-RAS gene activation in human bladder cancers. Cancer Genet Cytogenet 121:73–77CrossRefGoogle Scholar
  33. Public health impact of schistosomiasis (1993) disease and mortality. WHO Expert Committee on the Control of Schistosomiasis. Bull World Health Organ 71(6):657–662Google Scholar
  34. Rau KM, Chen HK, Shiu LY, Chao TL, Lo YP, Wang CC, Lin MC10, Huang CC (2016) Discordance of mutation statuses of epidermal growth factor receptor and K-ras between primary adenocarcinoma of lung and brain metastasis. Int J Mol Sci 17(4):E524. CrossRefGoogle Scholar
  35. Riely GJ, Marks J, Pao W (2009) KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc 6(2):201–205. CrossRefGoogle Scholar
  36. Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA (2010) Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol. 1 28(31):4769–4777. Epub 2010 Oct 4CrossRefGoogle Scholar
  37. Rusiecki JA1, De Roos A, Lee WJ, Dosemeci M, Lubin JH, Hoppin JA, Blair A, Alavanja MC (2004) Cancer incidence among pesticide applicators exposed to atrazine in the agricultural health study. J Natl Cancer Inst 96(18):1375–1382CrossRefGoogle Scholar
  38. Shim K, Kim K, Park B, Lee S, Choi J, Han W, Park E (1998) Increased serum levels of mutant P53 proteins in patients with colorectal cancer. J Korean Med Sci 13:44–48CrossRefGoogle Scholar
  39. Tokino T, Nakamura Y (2000) The role of P 53 target genes in human cancer. Crit Rev Oncol Hematol 33:1–6CrossRefGoogle Scholar
  40. Webster LR, McKenzie GH, Moriarty HT (2002) Organophosphate based pesticides and genetic damage implicated in bladder cancer. Cancer GenetCytogenet 133(2):112–117CrossRefGoogle Scholar
  41. Xifeng W, Jie Lin H, Barton G, Maosheng H, Jian G, Carol J, Etzel Amos CI, Dinney CP, Spitz MR (2007) Projecting individualized probabilities of developing bladder cancer in white individuals. J Clin Oncol 25(31):4974–4981CrossRefGoogle Scholar
  42. Xiong J, He M, Hansen K, Jackson CL, Breese V, Quddus MR, Sung CJ, Lomme MM, Lawrence WD (2016) The clinical significance of K-ras mutation in endometrial “surface epithelial changes” and their associated endometrial adenocarcinoma. Gynecol Oncol S0090-8258(16):30679–30675. Google Scholar
  43. Zarzour A, Selim M, Abd-Elsayed A, Hameed D, AbdelAziz M (2008) Muscle invasive bladder cancer in upper Egypt: the shift in risk factors and tumor characteristics. BMC Cancer 8:250–256CrossRefGoogle Scholar
  44. Zeimet AG, Riha K, Berger J, Widschwendter M, Hermann M, Daxenbichler G, Marth C (2000) New insights into P 53 regulations and gene therapy for cancer. Biochem Pharmacol 60:1153–1163CrossRefGoogle Scholar
  45. Zhu D, Xing D, Shen X, Liu J (2004) A method to quantitatively detect H-ras point mutation based on electrochemiluminescence. BiochemBiophys Res Commun 324:964–969CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018
corrected publication July 2018

Authors and Affiliations

  1. 1.Urology DepartmentAssiut UniversityAssiutEgypt
  2. 2.Forensic Medicine and Clinical Toxicology DepartmentAssiut UniversityAssiutEgypt
  3. 3.Microbiology DepartmentAssiut UniversityAssiutEgypt
  4. 4.Biochemistry DepartmentAssiut UniversityAssiutEgypt

Personalised recommendations