p53 p.Pro72Arg (rs1042522) and Mouse Double Minute 2 (MDM2) Single-Nucleotide Polymorphism (SNP) 309 Variants and Their Interaction in Chronic Lymphocytic Leukemia(CLL): A Survey in CLL Patients from Western Iran
Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The MDM2 and p53 are interacting proteins that play crucial roles in cell biology. Genetic variations of p53 and MDM2 (p53 codon 72 and MDM2 SNP30) have been identified in many cancers including CLL.
Materials and Methods: In this study, we sought to find the impact of two SNPs of p53 and MDM2 in the pathogenesis of CLL. A total of 100 CLL patients and 102 healthy controls were recruited. Genomic DNA was extracted, and genotyping was performed using the PCR-RFLP method. The allele and genotype associations were analyzed using the χ2 test. The gene-gene interaction analysis was studied using GMDR v0.9.
Results: Our study found the absence of a signiﬁcant difference between CLL patients and controls related to the allelic frequencies or genotypic distributions for both MDM2 SNP309 and p53 codon72. A significantly higher frequency of p53 C allele was found in patients with a disease duration of more than 36 compared to those less than 36 months. However, GMDR analysis suggests genetic interaction between the genes under study.
Conclusion: Our findings indicated each polymorphism of p53 codon72 and MDM2 (SNP309) was not a risk factor for CLL but the p53 C allele could be associated with the disease duration. Besides, the interaction between p53/MDM2 genotypes may confer susceptibility to CLL. Our study could be useful in genetic association studies of CLL and the role of gene-gene interactions in the susceptibility to the disease.
2. Damle RN, Wasil T, Fais F, et al. Chiorazzi, Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999; 94(6): 1840-7.
3. Zenz T, Mertens D, Kuppers R, et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010. 10(1): 37-50.
4. Molica S, Shanafelt TD, Giannarelli D, et al. The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients. Am J Hematol. 2016; 91(11): 1090-1095.
5. Amaya-Chanaga CI, Rassenti LZ. Biomarkers in chronic lymphocytic leukemia: Clinical applications and prognostic markers. Best Pract Res Clin Haematol. 2016; 29(1):79-89.
6. Wierda WG, Byrd JC, Abramson JS, et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020; 18(2): 185-217.
7. Soussi T, Lozano G. p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun. 2005; 331(3): 834-42.
8. Barnabas N, Shurafa M, Van Dyke DL, et al. Significance of p53 mutations in patients with chronic lymphocytic leukemia: a sequential study of 30 patients. Cancer. 2001; 91(2): 285-93.
9. Zenz T, Habe S, Denzel T, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood. 2009; 114(13): 2589-97.
10. Zenz T, Krober A, Scherer K, et al. Stilgenbauer, Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008; 112(8): 3322-9.
11. Dicker F, Herholz H, Schnittger S, et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia. 2009; 23(1): 117-24.
12. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002; 100(4): 1177-84.
13. Kaderi MA, Mansouri M, Zainuddin N, et al. Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia. Leuk Res. 2010; 34(3):335-9.
14. Maleki Y, Alahbakhshi Z, Heidari Z, et al. NOTCH1, SF3B1, MDM2 and MYD88 mutations in patients with chronic lymphocytic leukemia. Oncol Lett. 2019; 17(4): 4016-4023.
15. Nemati H, Rahimi Z, Bahrami G. The Xmn1 polymorphic site 5' to the (G)gamma gene and its correlation to the (G)gamma:(A)gamma ratio, age at first blood transfusion and clinical features in beta-thalassemia patients from Western Iran. Mol Biol Rep. 2010; 37(1):159-64.
16. Almeida BC, Kleine JP, Camargo-Kosugi CM, et al. Analysis of polymorphisms in codons 11, 72 and 248 of TP53 in Brazilian women with breast cancer. Genet Mol Res. 2016; 15(1).
17. Sun YF, Leu JD, Chen SM, et al. Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer. BMC Cancer. 2009; 9:13.
18. Xu HM, Xu LF, Hou TT, et al. GMDR: Versatile Software for Detecting Gene-Gene and Gene-Environ- ment Interactions Underlying Complex Traits. Curr Genomics. 2016; 17(5): 396-402.
19. Brown JR. Inherited predisposition to chronic lymphocytic leukemia. Expert Rev Hematol. 2008; 1(1): 51-61.
20. Lahiri O, Harris S, Packham G, et al. p53 pathway gene single nucleotide polymorphisms and chronic lymphocytic leukemia. Cancer Genet Cytogenet. 2007; 179(1): 36-44.
21. Gryshchenko I, Hofbauer S, Stoecher M, et al. Tinhofer, MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol. 2008; 26(14): 2252-7.
22. Dumont P, Leu JI,. Della Pietra AC, et al. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003; 33(3): 357-65.
23. Wu B, Guo D, Guo Y. Association between p53 Arg72Pro polymorphism and thyroid cancer risk: a meta-analysis. Tumour Biol. 2014; 35(1): 561-5.
24. Lu Y, Liu Y, Zeng J, et al. Association of p53 codon 72 polymorphism with prostate cancer: an update meta-analysis. Tumour Biol. 2014; 35(5): 3997-4005.
25. Geng P, Liao Y, Ruan Z, et al. Increased risk of cutaneous melanoma associated with p53 Arg72Pro polymorphism. PLoS One. 2015; 10(3): e0118112.
26. Zhu W, Lu L, Li Y, et al. The effects of p53 Arg72Pro polymorphism on glioma susceptibility: a meta-analysis. Tumour Biol. 2014; 35(4): 3725-30.
27. Chang Z,Yu X. Association between p53 codon 72 polymorphism and sarcoma risk among Caucasians. Tumour Biol. 2014; 35(5): 4807-12.
28. Alqumber MAA, Akhter N, Haque S, et al. Evaluating the association between p53 codon 72 Arg>pro polymorphism and risk of ovary cancer: a meta-analysis. PLoS One. 2014; 9(4): e94874.
29. Sturm I, Bosanquet AG, Hummel M, et al. In B-CLL, the codon 72 polymorphic variants of p53 are not related to drug resistance and disease prognosis. BMC Cancer. 2005; 5: 105.
30. Dong HJ, Fang C, Fan L, et al. MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL. Int J Cancer. 2012; 130(9): 2054-61.
31. Jones SN, Roe AE , Donehower LA, et al. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995; 378(6553): 206-8.
32. Barak Y, Juven T, Haffner R. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993; 12(2): 461-8.
33. Goldstein DB. Common genetic variation and human traits. N Engl J Med. 2009; 360(17): 1696-8.
34. Neuman RJ, Wasson J, Atzmon G, et al. Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population. PLoS One. 2010; 5(3): e9903.
|Issue||Vol 15 No 3 (2021)|
|CLL, p53, Mouse double minute 2 (MDM2), gene polymorphism, gene-gene interaction|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|