Impact of TP53 (rs1042522) and MDM2 (rs2279744) polymorphisms on cervical intraepithelial lesions and cervical cancer in North Macedonian women

Duvlis, Sotirija and Dabeski, Drage and Plaseska-Karanfilska, Dijana (2020) Impact of TP53 (rs1042522) and MDM2 (rs2279744) polymorphisms on cervical intraepithelial lesions and cervical cancer in North Macedonian women. European journal of human genetics.

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Abstract

Persistent human papillomavirus (HPV) infection is a major factor in the onset of cervical intraepithelial lesion (CIN), but additional factors are needed for their further progression to carcinoma (CCa).
Genetic variant in host cell cycle regulation genes such are single nucleotide polymorphisms (SNPs) rs1042522 within the codon 72 of TP53 and rs2279744 within MDM2 promoter genes are plausible factors that could influence cervical carcinogenesis conferring increased attenuation of p53 pathway.
The p53 tumour suppressor is gate keeper of cell cycle that regulates cellular pathways such as DNA repair, apoptosis, angiogenesis and is important defence mechanism against cancer onset and progression. The C to G base substitution in codon 72 replacing amino acid Proline with Arginine is considered to produce a more vulnerable variant of p53.
high risk HPV E6 oncoprotein binds to p53 and this interaction with rs1042522 variant is even stronger that additionally abrogates p53 function leading to its degradation through ubiquitin dependent pathway.

MDM2 oncoprotein is negative regulator of p53 tumour suppression. The variant rs2279744 in its promoter’s region could influence cervical carcinogenesis increasing its affinity of the Sp1 transcription factor. Objective: We investigated the association of these SNPs with the CIN and CCa among women from the Republic of North Macedonia.
Using a multiplex PCR SNaPShot analysis, we genotyped rs1042522 and rs2279744 in 131 women with CIN or CCa and 110 cytologically and Human papillomavirus negative women.
The allele and genotype frequencies of the variants were analysed using х2 –test in SISA statistic software.
The TP53 rs1042522 and MDM2 rs2279744 polymorphic variants showed no association with initiation and development of CIN and CCa. No significant difference in either genotype or allelic frequencies for rs1042522 and rs2279744 between cases and control was found.
Stratification of cases group based on grade of the lesion, revelled lower frequency of CC genotype and C allele of rs1042522 in CIN2+ and CCa compared to CIN1 [GG vs CC; p=0.001, OR=0.4; CG vs CC; p=0.04, OR=0.03 and CG+ GG vs CC; p=0.004, OR=0.2]. Furthermore, GG genotype and G allele of rs2279744 showed significantly lower frequency in CIN2+ and CCa cases then in CIN1 [G vs T p=0.02, OR=0.52; GG vs TT; p=0.04, OR=0.29; ТТ vs ТG+GG; p=0.007, OR=0.34].

CONCLUSION

The Arg variant of rs1042522 and T allele/TT genotype of rs2279744 are associated with progression of CIN1 to CIN2+ or CCa and may be used as prediction markers in CCa management. Still, clinical importance of these variants warrants further validation in large and more comprehensive studies.

Item Type:	Article
Subjects:	Medical and Health Sciences > Basic medicine
Divisions:	Faculty of Mechanical Engineering
Depositing User:	Sotirija Duvlis
Date Deposited:	20 Jun 2023 12:33
Last Modified:	20 Jun 2023 12:33
URI:	https://eprints.ugd.edu.mk/id/eprint/31948

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