p53 Mutation Possibility and Food Dietary Containing Heavy Metals

Document Type : Review Article


1 Department of Cellular and Molecular Biology, Faculty of Basic Science, Azarbaijan Shahid Madani University, Tabriz, Iran & Department of Molecular Biology and Cancer Research, Azarbaijan Shahid Madani University, Tabriz, Iran

2 Department of Cellular and Molecular Biology, Faculty of Basic Science, Azarbaijan Shahid Madani University, Tabriz, Iran


Background: Several types of cancer have mutations in the tumor suppressor gene p53. Environmental mutagens such as heavy metals play an undeniable role in p53 mutations and leave the mutational fingerprint on the TP53 gene. Therefore, the study of p53 mutation spectra can reflect the past heavy metals exposure.
Results: The current study was found interesting results by reviewing the previous data published in the databases. These results were obtained by comparing the common mutational profile between Iran, India, and Pakistan, and the association of these mutations with metals. The mutations in codons 146 (TGG→ TGA, Trp→ Stop), 214 (CAT→CGT, His→ Arg), and 249 (AGG→AGT, Arg→ Ser) were common in both India and Iran, due to the contamination by zinc and arsenic; arsenic and copper; cadmium, arsenic, nickel, and copper poisoning, respectively. Moreover, the mutations in codons 248 (CGG→ CAG, Arg→ Gln), 220 (TAT→ TGT, Tyr→ Cys), 248 (CGG→ TGG, Arg→ Trr), and 273 (CGT→ CAT, Arg→ His) were common among these three countries that could be related to poisoning with arsenic and zinc; arsenic; copper and arsenic; zinc and arsenic, respectively. These results can give a possible explanation for the cause of mutational similarities in these three areas, which can help identify the cause of high rates of p53 mutation and cancer control in these areas.
Conclusion: However, concerning the effects of other environmental factors, we definitely cannot explain the cause of these mutations among the heavy metals mentioned, since it requires more detailed studies.


  1. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019. The 2020; 396(10258):1204-22. doi: 10.1016/S0140-6736(20)30925-9.
  2. Mahurpawar effects of heavy metals on human health. International Journal of Research-‌Granthaalayah. 2015; 3(9):1-7. doi: 10.29121/
  3. Kang R, Kroemer G, Tang D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. 2019; 133:162- doi: 10.1016/j.freeradbiomed.2018.05.074.
  4. Berniyanti T, Palupi R, Kriswandini IL, Bramantoro T, Putri IL. Suitability of MDA, 8-OHdG and wild-type p53 as genotoxic biomarkers in metal (Co, Ni and Cr) exposed dental technicians: a cross-sectional study. BMC Oral Health. 2020; 20(1):65. doi: 10.1186/
  5. Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O., Arslan B. (Eds). Poisoning in the Modern World-New Tricks for an Old Dog? Intechopen; London, UK: 2019. doi: 10.5772/INTECHOPEN. 82511.
  6. Monastero RN, Vacchi-Suzzi C, Marsit C, Demple B, Meliker JR. Expression of genes involved in stress, toxicity, inflammation, and autoimmunity in relation to cadmium, mercury, and lead in human blood: a pilot study. Toxics. 2018;6(3):35. doi: 10.3390/toxics6030035.
  7. Sugiyama M. Role of cellular antioxidants in metal-induced damage. Cell biology and toxicology. 1994; 10(1):1-22. doi: 10.1007/BF00757183.
  8. Genchi G, Sinicropi MS, Lauria G, Carocci A, Catalano A. The effects of cadmium toxicity. Int J Environ Res Public Health. 2020; 17(11):3782. doi: 10.3390/ijerph17113782.
  9. Shan Z, Wei Z, Shaikh ZA. Suppression of ferroportin expression by cadmium stimulates proliferation, EMT, and migration in triple-negative breast cancer cells. Toxicol Appl Pharmacol. 2018; 356:36-43. doi: 10.1016/j.taap. 2018.07.017.
  10. Zhou X, Hao Q, Lu H. Mutant p53 in cancer therapy-the barrier or the path. J Mol Cell Biol. 2019; 11(4):293-305. doi: 10.1093/jmcb/mjy072.
  11. Kim MP, Lozano G. Mutant p53 partners in crime. Cell Death Differ. 2018; 25(1):161-168. doi: 10.1038/cdd.2017.185.
  12. Tang Q, Su Z, Gu W, Rustgi AK. Mutant p53 on the path to metastasis. Trends Cancer. 2020; 6(1):62-73. doi: 10.1016/j.trecan.2019.11.004. 
  13. Rickson R, Deeks L, Graves A, Harris J, Kibblewhite M, Sakrabani R. Input constraints to food production: the impact of soil degradation. Food Security. 2015;7(2):351-64. doi: 1007/
  14. Chanda A, Akhand A, Das A, Hazra S. Cr, Pb and Hg contamination on agricultural soil and paddy grain after irrigation using metropolitan sewage effluent. J Appl Environ Biol Sci. 2011; 1(10):464-9.
  15. Gayathri V, Revathi K. Seasonal variations of heavy metal distribution in waters and green mussels of ennore and royapuram estuaries, tamilnadu, India. Nature Environment and Pollution Technology. 2013; 12(3):483-86.
  16. Nawaz A, Khurshid K, Arif MS, Ranjha A. Accumulation of heavy metals in soil and rice plant (Oryza sativa L.) irrigated with industrial effluents. Int J Agric Biol. 2006; 8(3):391-3.
  17. Noreen M, Shahid M, Iqbal M, Nisar J. Measurement of cytotoxicity and heavy metal load in drains water receiving textile effluents and drinking water in vicinity of drains. Measurement. 2017; 109: 88-99. doi: 10.1016/j.measurement.2017.05.030.
  18. Shaheen A, Iqbal J, Hussain S. Adaptive geospatial modeling of soil contamination by selected heavy metals in the industrial area of Sheikhupura, Pakistan. Int J Environ Sci Technol. 2019; 16(1):4447-64. doi: 1007/s13762-018-1968-4.
  19. Ahmad SZN, Wan Salleh WN, Ismail AF, Yusof N, Mohd Yusop MZ, Aziz F. Adsorptive removal of heavy metal ions using graphene-based nanomaterials: Toxicity, roles of functional groups and mechanisms. Chemosphere. 2020; 248:126008. doi: 10.1016/j.
  20. Hartwig Metal interaction with redox regulation: an integrating concept in metal carcinogenesis? Free Radic Biol Med. 2013; 55:63-72. doi: 10.1016/j.freeradbiomed.2012.11. 009.
  21. Cheng TF, Choudhuri S, Muldoon-Jacobs K. Epigenetic targets of some toxicologically relevant metals: a review of the literature. J Appl Toxicol. 2012; 32(9):643-53. doi: 10.1002/jat. 2717.
  22. Chervona Y, Arita A, Costa M. Carcinogenic metals and the epigenome: understanding the effect of nickel, arsenic, and chromium. Metallomics. 2012; 4(7):619-27. doi: 10.1039/c2mt20033c.
  23. Hainaut P, Mann K. Zinc binding and redox control of p53 structure and Antioxid Redox Signal. 2001;3(4):611-23. doi: 10.1089/15230860152542961.
  24. Hainaut P, Milner J. A structural role for metal ions in the "wild-type" conformation of the tumor suppressor protein p53. Cancer Res. 1993; 53(8):1739-42. PMID: 8467489.
  25. Hainaut P, Rolley N, Davies M, Milner J. Modulation by copper of p53 conformation and sequence-specific DNA binding: role for Cu (II)/ Cu(I) redox mechanism. Oncogene. 1995; 10(1): 27-32. PMID: 7824276.
  26. Staib F, Hussain SP, Hofseth LJ, Wang XW, Harris CC. TP53 and liver carcinogenesis. Hum Mutat. 2003; 21(3):201-16. doi: 10.1002/humu. 10176. 
  27. Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, et al. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA. 2000 Nov 7;97(23):12770-5. doi: 10.1073/pnas. 220416097. 
  28. Steinbrueck A, Sedgwick AC, Brewster JT, Yan KC, Shang Y, Knoll DM, et al. Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents. Chem Soc Rev. 2020; 49(12):3726-3747. doi: 10.1039/c9cs00373h. 
  29. Bridge G, Rashid S, Martin SA. DNA mismatch repair and oxidative DNA damage: implications for cancer biology and treatment. Cancers. 2014; 6(3):1597-614. doi: 10.3390/cancers6031597.
  30. Dizdaroglu Oxidatively induced DNA damage: mechanisms, repair and disease. Cancer letters. 2012; 327(1-2):26-47. doi: 10.1016/j.canlet. 2012.01.016.
  31. Hainaut P, Milner J. Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Cancer Res. 1993; 53(19): 4469-73. PMID: 8402615.
  32. Shi T, Dansen TB. Reactive Oxygen Species Induced p53 Activation: DNA Damage, Redox Signaling, or Both? Antioxid Redox Signal. 2020; 33(12):839-859. doi: 10.1089/ars.2020. 8074.
  33. Kim DH, Kundu JK, Surh YJ. Redox modulation of p53: mechanisms and functional significance. Mol Carcinog. 2011; 50(4):222-34. doi: 10.1002/20709.
  34. Augustyn KE, Merino EJ, Barton JK. A role for DNA-mediated charge transport in regulating p53: Oxidation of the DNA-bound protein from a distance. Proceedings of the National Academy of Sciences. 2007; 104(48):18907-12. doi: 1073/pnas.0709326104.
  35. Schaefer KN, Barton JK. DNA-mediated oxidation of p53. Biochemistry. 2014; 53(21):
    3467-75. doi: 10.1021/bi5003184. 
  36. Jena NR. DNA damage by reactive species: Mechanisms, mutation and repair. J Biosci. 2012; 37(3):503-17. doi: 10.1007/s12038-012-9218-2. 
  37. Tapio S, Grosche B. Arsenic in the aetiology of cancer. Mutat Res. 2006; 612(3):215-246. doi: 10.1016/j.mrrev.2006.02.001. 
  38. Yoshida T, Yamauchi H, Fan Sun G. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review. Toxicol Appl Pharmacol. 2004; 198(3): 243-52. doi: 10.1016/j.taap.2003.10.022.
  39. Hsu CH, Yang SA, Wang JY, Yu HS, Lin SR. Mutational spectrum of p53 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan. Br J Cancer. 1999; 80(7):1080-6. doi: 10.1038/sj.bjc.6690467.
  40. Mass MJ, Wang L. Alterations of methylation of the tumor suppressor gene p53: insights into potential mechanisms of arsenic carcinogenesis. In: Abernathy CO, Calderon RL, Chappell WR, editors. Arsenic: Exposure and Health Effects. New York: Chapman & Hall; 1997. p. 338-48.
  41. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992; 89(16):7491-5. doi: 10.1073/pnas.89. 16.7491.
  42. Mahipal SS, Rajeev K. Arsenic-induced neurotoxic & carcinogenic effects on humans. Open Acc J of Toxicol. 2018; 3(4): 555617. doi: 10.19080/OAJT.2018.03.555617.
  43. Wang Z, Tang M. Research progress on toxicity, function, and mechanism of metal oxide nanoparticles on vascular endothelial cells. J Appl Toxicol. 2021 May;41(5):683-700. doi: 10.1002/jat.4121.
  44. Tkeshelashvili LK, McBride T, Spence K, Loeb LA. Mutation spectrum of copper-induced DNA damage. J Biol Chem. 1991; 266(10):6401-6. PMID: 1618873.
  45. VanLandingham JW, Fitch CA, Levenson CW. Zinc inhibits the nuclear translocation of the tumor suppressor protein p53 and protects cultured human neurons from copper-induced neurotoxicity. Neuromolecular Med. 2002; 1(3):171-82. doi: 10.1385/NMM:1:3:171.
  46. Andrews Iron homeostasis: insights from genetics and animal models. Nat Rev Genet. 2000; 1(3):208-17. doi: 10.1038/35042073.
  47. Knobel Y, Weise A, Glei M, Sendt W, Claussen U, Pool-Zobel BL. Ferric iron is genotoxic in non-transformed and preneoplastic human colon cells. Food Chem Toxicol. 2007; 45(5):804-11. doi: 10.1016/j.fct.2006.10.028.
  48. Shen J, Sheng X, Chang Z, Wu Q, Wang S, Xuan Z, Li D, Wu Y, Shang Y, Kong X, Yu L, Li L, Ruan K, Hu H, Huang Y, Hui L, Xie D, Wang F, Hu R. Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell Rep. 2014; 7(1):180-93. doi: 10.1016/j.celrep.2014.02.042.
  49. Lee JH, Jang H, Cho EJ, Youn HD. Ferritin binds and activates p53 under oxidative stress. Biochem Biophys Res Commun. 2009; 389(3):
    399-404. doi: 10.1016/j.bbrc.2009.08.125.
  50. Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez MA, McKnight SL. NPAS2: a gas-responsive transcription factor. 2002; 298(5602):2385-7. doi: 10.1126/science. 1078456.
  51. Marrogi AJ, Khan MA, van Gijssel HE, Welsh JA, Rahim H, Demetris AJ, Kowdley KV, Hussain SP, Nair J, Bartsch H, Okby N, Poirier MC, Ishak KG, Harris CC. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular J Natl Cancer Inst. 2001; 93(21):1652-5. doi: 10.1093/jnci/93.21.1652.
  52. Meneghini Iron homeostasis, oxidative stress, and DNA damage. Free Radic Biol Med. 1997; 23(5):783-92. doi: 10.1016/s0891-5849 (97)00016-6.
  53. Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, et al. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991; 254(5034):1001-3. doi: 10.1126/science.1948068.
  54. Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Harrington AM, et al. Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J Natl Cancer Inst. 1999; 91(1):86-8. doi: 10.1093/jnci/91.1.86.
  55. Filipic Mechanisms of cadmium induced genomic instability. Mutat Res. 2012; 733(1-2):69-77. doi: 10.1016/j.mrfmmm.2011.09.002.
  56. Liu J, Qu W, Kadiiska MB. Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol. 2009; 238(3):209-14. doi: 10.1016/j.taap.2009.01.029. 
  57. Méplan C, Mann K, Hainaut P. Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J Biol Chem. 1999; 274(44):31663-70. doi: 10.1074/jbc.274.44. 31663. 
  58. Hartwig Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signal. 2001; 3(4):625-34. doi: 10.1089/15230860152
  59. Zhou T, Jia X, Chapin RE, Maronpot RR, Harris MW, Liu J, Waalkes MP, Eddy EM. Cadmium at a non-toxic dose alters gene expression in mouse testes. Toxicol Lett. 2004; 154(3):191-200. doi: 10.1016/j.toxlet.2004.015.
  60. Hsieh LL, Wang PF, Chen IH, Liao CT, Wang HM, Chen MC, Chang JT, Cheng AJ. Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese. Carcinogenesis. 2001; 22(9):1497-503. doi: 10.1093/carcin/22.9.1497. 
  61. Costa M, Davidson TL, Chen H, Ke Q, Zhang P, Yan Y, Huang C, Kluz T. Nickel carcinogenesis: epigenetics and hypoxia signaling. Mutat Res. 2005; 592(1-2):79-88. doi: 10.1016/j.mrfmmm. 2005.06.008.
  62. Cameron KS, Buchner V, Tchounwou PB. Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review. Rev Environ Health. 2011; 26(2):81-92. doi: 10.1515/reveh.2011.012.
  63. Anttila A, Pukkala E, Aitio A, Rantanen T, Karjalainen S. Update of cancer incidence among workers at a copper/nickel smelter and nickel refinery. Int Arch Occup Environ Health. 1998; 71(4):245-50. doi: 10.1007/s004200050276. 
  64. Clemens F, Landolph JR. Genotoxicity of samples of nickel refinery dust. Toxicological sciences: an official journal of the Society of Toxicology. 2003; 73(1):114-23. doi: 10.1093/
  65. Kiilunen M, Utela J, Rantanen T, Norppa H, Tossavainen A, Koponen M, Paakkulainen H, Aitio A. Exposure to soluble nickel in electrolytic nickel refining. Ann Occup Hyg. 1997; 41(2):167-88. doi: 10.1016/s0003-4878
  66. Hostynek Nickel-induced hypersensitivity: etiology, immune reactions, prevention and therapy. Arch Dermatol Res. 2002; 294(6):249-67. doi: 10.1007/s00403-002-0319-x. 
  67. Kawanishi S, Oikawa S, Inoue S, Nishino K. Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides. Environ Health Perspect. 2002; 110 Suppl 5(Suppl 5):789-91. doi: 10.1289/ehp.02110s5789.
  68. Gupta AD, Dhundasi SA, Ambekar JG, Das KK. Effect of l-ascorbic acid on antioxidant defense system in testes of albino rats exposed to nickel sulfate. J Basic Clin Physiol Pharmacol. 2007; 18(4):255-66. doi: 10.1515/jbcpp.2007.18.4. 255.
  69. Kasprzak KS, Sunderman FW Jr, Salnikow K. Nickel carcinogenesis. Mutat Res. 2003; 533(1-2):67-97. doi: 10.1016/j.mrfmmm.2003.08.021. 
  70. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004; 44:239-67. doi: 10.1146/annurev.pharmtox.44.101802. 121851.
  71. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006; 160(1):1-40. doi: 10.1016/j.cbi.
  72. Maehle L, Metcalf RA, Ryberg D, Bennett WP, Harris CC, Haugen A. Altered p53 gene structure and expression in human epithelial cells after exposure to nickel. Cancer Res. 1992; 52(1):218-21. PMID: 1727381.
  73. Haugen A, Maehle L, Mollerup S, Rivedal E, Ryberg D. Nickel-induced alterations in human renal epithelial cells. Environ Health Perspect. 1994; 102(3):117-8. doi: 10.1289/ehp.94102s3117.
  74. Chiou YH, Wong RH, Chao MR, Chen CY, Liou SH, Lee H. Nickel accumulation in lung tissues is associated with increased risk of p53 mutation in lung cancer patients. Environ Mol Mutagen. 2014 Oct;55(8):624-32. doi: 10.1002/em.21867.
  75. Gerster-Bentaya M. Nutrition-sensitive urban agriculture. Food Sec. 2013;5(5):723-37. doi: 1007/s12571-013-0295-3.
  76. Kim HS, Kim YJ, Seo YR. An Overview of Carcinogenic Heavy Metal: Molecular Toxicity Mechanism and Prevention. J Cancer Prev. 2015; 20(4):232-40. doi: 10.15430/JCP.2015.20.4.232.
  77. Sá I, Semedo M, Cunha ME. Kidney cancer. Heavy metals as a risk factor. PortoBiomed J. 2016; 1(1):25-8. doi: 10.1016/j.pbj.2016.03.006.
  78. Goering PL, Barber DS. Hepatotoxicity of copper, Iron, Cadmium, and arsenic A2-McQueen, Charlene A. Comprehensive Toxicology (Second Edition). Oxford: Elsevier. 2010; 501-26. doi:10.1016/B978-0-08-046884-6.01022-8.
  79. Waseem A, Arshad J, Iqbal F, Sajjad A, Mehmood Z, Murtaza G. Pollution status of Pakistan: a retrospective review on heavy metal contamination of water, soil, and vegetables. Biomed Res Int. 2014; 2014:813206. doi: 10.1155/2014/813206. 
  80. Tahir MA, Rasheed H, Imran S. Water quality status in rural areas of Pakistan; Islamabad: Pakistan Council of Research in Water Resources. 2010.
  81. Bhatti SS, Kumar V, Singh N, Sambyal V, Singh J, Katnoria JK, et al. Physico-chemical properties and heavy metal contents of soils and kharif crops of punjab, India. Procedia Environ Sci. 2016; 35:801-8. doi: 1016/j.proenv.2016.07. 096.
  82. Mohankumar K, Hariharan V, Rao NP. Heavy Metal Contamination in Groundwater around Industrial Estate vs Residential Areas in Coimbatore, India. J Clin Diagn Res. 2016; 10(4):BC05-7. doi: 10.7860/JCDR/2016/15943. 7527.
  83. Bhagure GR, Mirgane SR. Heavy metal concentrations in groundwaters and soils of thane region of maharashtra, India. Environ Monit Assess. 2011; 173(1-4):643-52. doi: 10.1007/s10661-010-1412-9.
  84. Khan K, Lu Y, Khan H, Ishtiaq M, Khan S, Waqas M, Wei L, Wang T. Heavy metals in agricultural soils and crops and their health risks in Swat District, northern Pakistan. Food Chem Toxicol. 2013; 58:449-58. doi: 10.1016/j.fct. 2013.05.014.
  85. Mahmood A, Malik RN. Human health risk assessment of heavy metals via consumption of contaminated vegetables collected from different irrigation sources in Lahore, Pakistan. Arabian Journal of Chemistry. 2014; 7(1):91-9. doi: 1016/j.arabjc.2013.07.002.
  86. Rehman K, Fatima F, Waheed I, Akash MSH. Prevalence of exposure of heavy metals and their impact on health consequences. J Cell Biochem. 2018; 119(1):157-184. doi: 10.1002/jcb.26234.
  87. Luevano J, Damodaran C. A review of molecular events of cadmium-induced carcinogenesis. J Environ Pathol Toxicol Oncol. 2014; 33(3):183-94. PMID: 25272057.
  88. Rodin SN, Rodin AS. Origins and selection of p53 mutations in lung carcinogenesis. Semin Cancer Biol. 2005; 15(2):103-12. doi: 10.1016/j. semcancer.2004.08.005. 
  89. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002; 21(48):7435-51. doi: 10.1038/sj.1205803. 
  90. Morita A, Ariyasu S, Ohya S, Takahashi I, Wang B, Tanaka K, et al. Evaluation of zinc (II) chelators for inhibiting p53-mediated apoptosis. Oncotarget. 2013; 4(12):2439-50. doi: 10.18632/
  91. Shibata A, Ohneseit PF, Tsai YC, Spruck CH 3rd, Nichols PW, Chiang HS, et al. Mutational spectrum in the p53 gene in bladder tumors from the endemic area of black foot disease in Taiwan. 1994; 15(6):1085-7. doi: 10.1093/carcin/15.6.1085. 
  92. Moore LE, Smith AH, Eng C, DeVries S, Kalman D, Bhargava V, et al. P53 alterations in bladder tumors from arsenic and tobacco exposed patients. 2003; 24(11): 1785-91. doi: 10.1093/carcin/bgg136.
  93. Saranath D, Tandle AT, Teni TR, Dedhia PM, Borges AM, Parikh D, et al. p53 inactivation in chewing tobacco-induced oral cancers and leukoplakias from India. Oral Oncol. 1999; 35(3):242-50. PMID: 10621843.
  94. Pouladi N, HosseinpourFeizi M-A, Montasser Kouhsari S, Farajzadeh D, Khani H, Ravanbakhsh Gavgani R, et al. Molecular epidemiology of breast cancer among iranian-azeri population based on P53 research. Journal of Kerman University of Medical Sciences. 2018; 25(3):228-42.
  95. Eachkoti R, Hussain I, Afroze D, Aejazaziz S, Jan M, Shah ZA, et al. BRCA1 and TP53 mutation spectrum of breast carcinoma in an ethnic population of Kashmir, an emerging high-risk area. Cancer Lett. 2007; 248(2):308-20. doi: 10.1016/j.canlet.2006.08.012. 
  96. Khaliq S, Hameed A, Khaliq T, Ayub Q, Qamar R, Mohyuddin A, et al. P53 mutations, polymorphisms, and haplotypes in Pakistani ethnic groups and breast cancer patients. Genet Test. 2000; 4(1):23-9. doi: 10.1089/109065700316435. 
  97. Biramijamal F, Allameh A, Mirbod P, Groene HJ, Koomagi R, Hollstein M. Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran. Cancer Res. 2001; 61(7):3119-23. PMID: 11306496.
  98. Nejad AL, Yaghoobi MM. Mutation analysis of TP53 tumor suppressor gene in colorectal cancer in patients from Iran (Kerman Province). Iran J Basic Med Sci. 2012; 15(1):683-90. PMID: 23492839.
  99. Vijayaraman KP, Veluchamy M, Murugesan P, Shanmugiah KP, Kasi PD. p53 exon 4 (codon 72) polymorphism and exon 7 (codon 249) mutation in breast cancer patients in southern region (Madurai) of Tamil Nadu. Asian Pac J Cancer Prev. 2012; 13(2):511-6. doi: 10.7314/apjcp. 2012.13.2.511. 
  100. Mohamadkhani A, Naderi E, Sharafkhah M, Fazli HR, Moradzadeh M, Pourshams A. Detection of TP53 R249 mutation in Iranian patients with pancreatic cancer. J Oncol. 2013; 2013:738915. doi: 10.1155/2013/738915.