The Common polymorphisms in P21 and MDM2 genes as a risk factor for susceptibility and poor prognosis of non-small cell lung cancer in Iraqi population
Main Article Content
Keywords
NSCLC, gene, polymorphism, P21, MDM2, Iraq
Abstract
Background: Cyclin-dependent kinase inhibitor (P21/WAFI) and murine double minute 2 (MDM2) genes regulate cell growth. In malignant tumors, altered expression of these gene products is associated with poor prognosis, this study was designed to determine genotyping of P21 and MDM2.
Methods: This case-control study included 140 lung cancer patients (101 males and 39 females) diagnosed with non-small cell lung carcinoma, matched with 150 healthy individuals(105 males and 45 females). The study was done between 2018 to 2022. The current study aimed to investigate P21-rs1801270 and MDM2-rs2279744 genes polymorphisms with lung cancer risk in the Iraqi population using the PCR-RFLP technique.
Results: Compared with the P21-98 C and MDM2-309T genotypes, we found that P21-98A and MDM2-309G variants were associated with a high risk of NSCLC in Iraqi patients (OR= 5.0, C.I= 3.2-14.2, P<0.0001) for AA and (OR= 6.7, C.I= 4.0-12.4, P<0.0001)for GG. Also, AA and GG genotypes were associated with poor prognosis and significant associations were observed with a stage (p= 0.02) and metastasis status (p =0.003) for the P21 gene, (p= 0.01) and (p= 0.04) for the MDM2 gene respectively of NSCLC in elderly and smokers. Our results obviously showed the multiplicative interaction of P21 AA and MDM2 GG genotypes in the risk of developing lung cancer.
Conclusions: The presence of AA variant alleles for p21 and GG for MDM2 increased the risk of lung cancer in males mainly those smokers older than 45. For this reason, these gene mutations may have a role as markers for susceptibility to lung cancer in those groups of people.
References
2. Habib OS, Al-Diab JM, Mohsin AA, Al-Elwe WM, Hasan JG, Al-Haroon SS, et al (2010) Experience and outcome of population based cancer registration in Basrah-Southern Iraq in 2005-2008. Asian Pac J Cancer Prev 11: 1151-1154. https://www.researchgate.net/publication/49660245
3. Fang L, Huayu H, Bin Q, Ying J, Kelin S, Qi X (2019) Clinicopathological characteristics and prognosis of lung cancer in young patients aged 30 years and younger. Journal of Thoracic Disease 11 (10): 4282-4291. http://dx.doi.org/10.21037/jtd.20 4. Torok S, Hegedus B, Laszlo V, Hoda MA, Ghanim B, BergerW, et al (2011) Lung cancer in never smokers.Future Oncol 7:1195-211. DOI:10.1007/978-3-319-24223-1-3.
5. Sivonova MK, Vilckova M, Kliment J, Mahmood S, jurecekova1 J, Dusenkova S, et al (2015) Association of p53 and p21 p\olymorphisms with prostate cancer. Biomedical Reports 3: 707-714. DOI: 10.3892/br.2015.496
6. Bahar S, and Sinem U (2019) p21 in Cancer Research. Cancers 11: 1178. DOI: 10.3390/cancers11081178
7. Tahereh SF, Gholamreza M, Ahmad YM, Rezvan T (2015) p21 Gene Expression Evaluation in Esophageal Cancer Patients. Gastrointest Tumors 2:144–164. DOI.org/10.1159/000441901
8. Roman K, Markus W, Christine B (2006) Binding of p53 to the Central Domain of Mdm2 Is Regulated by Phosphorylation. Journal of Biological Chemistry 281 (39): 28575-28583. DOI: 10.1074/jbc.M513311200
9. Moll UM, Petrenko O (2003) The MDM2-p53 interaction. Mol Cancer Res 1:1001-1008. https://pubmed.ncbi.nlm.nih.gov/14707283/
10. Lind H, Zienolddiny S, Ekstrøm PO, Skaug V,Haugen A (2006) Association of a functional polymorphism in the promoter of the MDM2 gene with risk of non-small cell lung cancer. Int J Cancer 119: 718-21.DOI: 10.1002/ijc.21872
11. Hui WC, Daniel N, Serena C, San SL, Huihua L, Li YS et al (2010) Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among non-smoking Chinese women in Singapore. BMC Cancer 10: 88. http://www.biomedcentral.com/1471-2407/10/88
12. Al-janabi AM, Rahim AI., Faris SA, Al-khafaji SM, Jawad D (2020) Prevalence of Y chromosome microdeletion in azoospermic infertile males of Iraqi population. Journal of Genetics 99:18. DOI. 10.1007/s12041-020-1181-3
13. Datong Z, Yanping C, Caijie G, Yongyue W, Guochun C, Nan L, Yayi H, Xiuqin J, Jianjun W (2014) Polymorphisms of p53 and MDM2 genes are associated with severe toxicities in patients with non-small cell lung cancer. Cancer Biology & Therapy 15: 1542-51. DOI: 10.4161/15384047.2014.956599.
14. Gauderman WJ, Murcray C, Gilliland F, Conti DV (2007) Testing association between disease and multiple SNPs in a candidate gene. Genet Epidemiol 31:383-395 DOI: 10.1002/gepi.20219.
15. Islami E, Torre LA, Jemal A (2015) Global trends of lung cancer mortality and smoking prevalence.
Transl Lung Cancer Res 4:327-38. DOI: 10.3978/j.issn.2218-6751.2015.08.04
16. Buthainah AI, Al-Humaish S, Mohammed AI, Al-Obaide MA (2018) Tobacco Smoking, Lung Cancer, and Therapy in Iraq: Current Perspective. Frontiers in Public Health. 6: 311. DOI: 10.3389/fpubh.2018.00311
17. Dilshad A, Bekairy AK, Tamimi W (2015) MDM2 (RS769412) G>a Polymorphism in Cigarette Smokers: AClue for the Susceptibility to Smoking and Lung Cancer Risk. Asian pacific J. of cancer Prev 16: 4057-4059. DOI: 10.7314/apjcp.2015.16.9.4057.
18. Al Reza H, Anamika WJ, Chowdhury MK, Mostafa MG, Aftab Uddin M (2020) A cohort study on the association of MDM2 SNP309 with lung cancer risk in Bangladeshi population. Korean J Intern Med 35:672-681. DOI: 10.3904/kjim.2018.125
19. Park HJ, Yu E, Shim YH (2006) DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma. Cancer Lett. 233:271-8, DOI: 10.1016/j.canlet.2005.03.017
20. Wang H, Ma K (2015) Association between MDM2 rs769412 and rs937283 polymorphisms with alcohol drinking and laryngeal carcinoma risk. Int J Clin Exp Pathol 8: 7436-7440. PMID: 26261649
21. Zhang X, Miao X, Guo Y, Tan W, Zhou Y, Sun T, Wang Y, Lin D (2006) Genetic Polymorphisms in Cell Cycle Regulatory Genes MDM2 and TP53 Are Associated With Susceptibility to Lung Cancer. Human Mutation 27(1):110-117, DOI: 10.1002/humu.20277.
22. Xie D, Linhua L, Kate H, Lin C, Cuicui X, Rongrong W, Yang S, Xiaoyi W, Lu W, Yongzhang L, Bin L (2014) Association of p53/p21 expression and cigarette smoking with tumor progression and poor prognosis in non-small cell lung cancer patients. Oncology Reports 12: 2517-2526. DOI: 10.3892/or.2014.3538
23. Liu F, Bo L, Younggag W, Xi C, Yu M, Lvnan Y, Tianfu W (2011) p21 codom 31 polymorphism associated with cancer among white people: evidence from a meta-analysis involving 78074 subjects. Mutagenesis 26: 513-521. DOI: 10.1093/mutage/ger010
24. Li S, Yang S, Rong F, Sally WT, David P M, Wei Z et al (2003) P53(codon72) and p21 (codon31) polymorphisms alter in vivo mRNA expression of p21. Lung Cancer 40: 259-266.DOI: 10.1016/s0169-5002(03)00081-3
25. Li S, Geoffrey L, Wei Z, Li LX, David PM, Sohee P et al (2003) No association between the p21 codon 31 serine-arginine polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 12:174-175. https://pubmed.ncbi.nlm.nih.gov/12582031/
26. Odilia P, Lutz E, Peter W, Torsten S, Dorota B, Thomas M et al (2007) Elevated risk of squamous-cell carcinoma of the lung in heavy smokers carrying the variant alleles of the TP53 Arg72Pro and p21 Ser31Arg polymorphisms. Lung Cancer 55: 25-34. DOI: 10.1016/j.lungcan.2006.09.006.
27. Ju WR, Jae WK, Noh HP, Yong SS, In Ae P, Sang-Yoon P et al (2004) p53 and p21 genetic polymorphisms and susceptibility to endometrial cancer. Gynecol Oncol 93:499-505.DOI: 10.1016/j.ygyno.2004.02.005.
28. Ya-Guang X, Ke-Yue D, Xiu-Lan S, Da-Fang C, Wei-Cheng Y, Yan S et al (2004) p53 polymorphism and p21WAF1/CIP1 haplotype in the intestinal gastric cancer and the precancerous lesions. Carcinogenesis 25:2201-2206.DOI: 10.1093/carcin/bgh229.
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