Abstract
Introduction: Protein p53 is encoded by tumor suppressor TP53, which regulates key cellular functions such as transcription, cell cycle arrest, DNA repair and apoptosis. Murine double minute 2 homolog (MDM2), a p53 transcribed protein, negatively regulates p53. A single nucleotide polymorphism (SNP) at codon 72 of TP53 (R72P, rs rs1042522) alters an amino acid, while an SNP T309G (rs2279744) polymorphism (SNPT309G) in the promoter region of MDM2 has been reported to modulate its transcription. p53 R72P and MDM2 SNPT309G have been reported to associate alone and or in combination with various carcinomas. In this study, we aimed to determine if p53 R72P and MDM2 SNPT309G polymorphism alone or in combination are associated with colon carcinoma incidence, tumor progression and/or patient survival in Swedish population. Materials and methods: We determined polymorphisms in 151 colon carcinoma patients and 188 healthy controls by PCR-Pyrosequencing. For statistical analysis, we applied logistic regression analysis, Chi square and multivariate Cox regression to determine incidence, progression of colon carcinoma and overall patient survival respectively. Statistical analyses were two sided. Results: We found that individual carriers of Arg/Pro and Pro/Pro+Pro/Arg (Pro/--) are at 1.72 (95% CI; 1.09-2.72), and 1.659(95% CI; 1.07-2.58) fold higher risk of developing colon carcinoma compared to the carriers of Arg/Arg individuals. We did not find association of MDM2 SNPT309G with incidence of colon carcinoma. No association was found between p53 and MDM2 polymorphisms and clinicopathological parameters, except for TT variant that was correlated with low-differentiated tumors. We also found that people with Arg/Pro and Pro/--- had significantly lower overall survival compared with the people having Arg/Arg variants (Arg/Pro, OR; 1.75, 95% CI; 1.09-2.75, Pro/---, OR; 1.7, 95% CI; 1.065-2.68), but MDM2 polymorphism was not associated with patient survival. In combined analysis, with reference to Arg/Arg+TG/GG, Pro/---+TG/GG was marginally correlated with colon carcinoma incidence (OR; 1.75, 95% CI; 0.99-3.11), while Pro/---+TT was significantly correlated with poor patient survival (OR; 2.03, 95% CI; 1.029-4.02). Conclusion: p53 R72P polymorphism is associated with the incidence of colon carcinoma and patient survival. p53 and MDM2 polymorphism appear to interact with each other and modify the association with colon carcinoma incidence and patients’ survival.
Highlights
Protein p53 is encoded by tumor suppressor TP53, which regulates key cellular functions such as transcription, cell cycle arrest, DNA repair and apoptosis
The best explanation of this came from the knowledge of different polymorphic variants of various genes; those involved in cell cycle control and DNA repair mechanism, and their frequency varies among different population. p53 is one of the most studied proteins that plays fundamental role in regulating basic cellular function and because of this, it is an important target protein to study different polymorphic variants of p53 for their association with various diseases including colon carcinomas [10,12,13,14,27]
A single nucleotide polymorphism (SNP) in Murine double minute 2 homolog (MDM2) (SNPT309G), a negative regulator of p53, alone or in combination with p53 has been reported to associate with different carcinomas and progression of disease [14,18,22,23,25,27,28,29,30]
Summary
Protein p53 is encoded by tumor suppressor TP53, which regulates key cellular functions such as transcription, cell cycle arrest, DNA repair and apoptosis. P53 R72P and MDM2 SNPT309G have been reported to associate alone and or in combination with various carcinomas. We aimed to determine if p53 R72P and MDM2 SNPT309G polymorphism alone or in combination are associated with colon carcinoma incidence, tumor progression and/or patient survival in Swedish population. An estimated numbers of new cases of CRC were 1.36 million and an estimated death of tolls about 700000, in 2012 alone. In Europe, estimated numbers of new cases of CRC were 447,136 and deaths 214,866 in the same year [1]. TP53 encodes a 53 KDa nuclear protein, p53, which functions as a transcription factor to regulate the expression of multiple proteins. Different polymorphic variants of TP53 can impact on p53 functions [8,9]
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