The Variant Allele Frequency of p53 Arg72Pro (rs1042522) Polymorphism: A Major Breast Cancer Susceptibility Factor in Saudi and Other Ethnic Groups

Egyptian Academic Journal of Biological Sciences is the official English language journal of the Egyptian Society for Biological Sciences, Department of Entomology, Faculty of Sciences Ain Shams University. C. Physiology & Molecular Biology journal is one of the series issued twice by the Egyptian Academic Journal of Biological Sciences, and is devoted to publication of original papers that elucidate important biological, chemical, or physical mechanisms of broad physiological significance. http://eajbsc.journals.ekb.eg/ Provided for non-commercial research and education use.


INTRODUCTION
Breast cancer causes high morbidity and mortality in females, globally (Parkin et al. 2001).Age of breast cancer occurrence in the Saudi population is highly skewed when compared with the USA.The number of breast cancers developed before the age of 40 in the Saudi population is almost four times that of USA (Ezzat et al. 1999).An early study has shown that ≤ 40 years of age is an independent risk factor for relapse in operable Saudi breast cancer patients (Elkum et al. 2007).
The global cancer incidence variation is primarily caused by genetic and environmental factors including ionizing radiations causing DNA damage and the loss of genomic integrity coupled with defective DNA repair system leading to elevated cancer risk.
Genetic changes impacting host DNA repair system significantly contribute to cancer susceptibility (de Jong et al. 2002).Single-nucleotide polymorphisms (SNPs) are the single base changes present in at least 1% population (Collins et al. 1999), having a minor individual effect but the additive impact of multiple SNPs over cancer onset and progression makes them a critical target for study (Perera and Weinstein 2000).
SNPs are known to reduce DNA repair capacity (DRC) rendering the host increasingly susceptible for cancer when compared with the population devoid of them (Wu et al. 2004).The reports on inter-individual variations in diverse populations are valuable in identifying candidate susceptibility alleles/ genotype contributing to carcinogenesis.
A number of risk factors like genetic susceptibility and estrogen hormone exposure are associated with breast carcinogenesis, however, the precise molecular mechanisms remain to be elucidated (Veronesi et al. 2005;Yager and Davidson 2006).
Early reports suggest that tumorigenesis is an outcome of several changes in oncogenes and tumor suppressor genes (Porter-Jordan and Lippman 1994; Bartkova et al. 1995).
Alterations in p53, regarded as the guardian of the genome, not only compromises a range of critical cellular processes including cell cycle arrest, DNA damage repair, apoptosis but may also promote cancer development (Bennett et al. 1999;Vogelstein et al. 2000;Brosh and Rotter 2009;Li et al. 2011).Not surprisingly, multiple reports show more than 50% of human tumors harboring p53 gene mutations (Bennett et al. 1999).Of 11 exons, the p53 tumor suppressor gene has the codon 72 polymorphism (rs1042522) located in exon 4 with a CGC to CCC transition, resulting in an arginine to proline amino acid substitution in amino acid position 72 (Arg72Pro).The two polymorphic variants have dissimilar biological effects and have been found linked with the carcinogenesis (Harris et al. 1986;Dumont et al. 2003;Zhou et al. 2007).This SNP, 1 among 25 SNPs, has the undetectably small individual effect but confers significant risk for breast cancer, cumulatively (Johnson et al. 2007).
SNPs have the potential to be used as next generation biomarkers, identifying the loci associated with intricate diseases.They can also be used to study genetic variations in drug metabolic pathways influencing individual responses to drugs (Lander and Schork 1994;Lander 1996;Risch and Merikangas 1996) (Kruglyak 1997).
The present study investigated the frequency distribution of p53 exon 4 Arg72Pro, CGC to CCC transition, rs1045522 polymorphism in normal healthy individuals, age and sex-matched with breast cancer cases, from Saudi Arabia.The frequency distribution of the Saudi population was compared with diverse epidemiologic studies stratified along the Asian and Caucasian race performed globally.The findings of the study may facilitate the large scale population screening based on the prevalence of susceptibility factor.

MATERIALS AND METHODS Selection of Studies:
PUBMED (Medline), the web of science and google database were used for research publications containing keywords "p53", "Arg72Pro", rs1045522 and ''polymorphism''.The inclusion criteria required case control or cohort studies conducted with human subjects, showing genotype frequencies for the control population.
Details like the name of the first author, year of publication, the number and race of the controls, inclusion/ exclusion criteria along with allelic/ genotypes distribution among controls were extracted.
Two studies in the Saudi Arabian population were not found consistent with the Hardy-Weinberg equilibrium (HWE) analysis.The genotype distribution of p53 (exon 4, Arg > Pro) in Saudi population showed the minor allele frequency (MAF) at 51% (Table 1).A significantly different MAF was found for Japan (p<0.0001),Jordan (p=0.0002),China (p<0.0001),Iran (p<0.0001),India (p=0.0023),Turkey (p<0.0001) and Taiwan (0.0307) ethnic populations, upon comparison of Saudi Arabian frequency with that of other Asian populations.
Interestingly, a significantly different MAF was found in every study in the Caucasian group except for Greece (p=0.1451)ethnic populations, while compared with Saudi Arabian frequency.

DISCUSSION
The genes and/ or their polymorphisms identified through genome-wide/ genetic association studies have markedly influenced the development of effective disease prevention programs as well as their novel treatment (Pearson and Manolio 2008).p53 plays an important role in many cellular functions like gene transcription, DNA repair and programmed cell death and the SNPs of p53 likely have an association with cancer susceptibility including breast cancer (Zhang et al. 2010).
The discrepant findings are likely based on the human genome diversity, resulting from multiple evolutionary and demographic events like migration, isolation and natural selection, impacting individual susceptibility variably across the populations (Balaresque et al. 2007;Barbujani and Colonna 2010;Henn et al. 2012).Recent evidence showing that SNPs may act as candidate genes significantly contribute to the cancer susceptibility, emphasizes the importance of information about the prevalence of variant genetic alleles in diverse populations.Early reports included in the current study to extract data of normal healthy subjects show significant differences in the distribution of p53 gene Arg72Pro polymorphism among diverse populations globally, stratified along Asian and Caucasian subgroups.Further, the present study showed significantly different MAF of p53 Arg72 SNP distribution in Saudi population when compared with other ethnic groups.Among Asian subgroup, significantly different MAF was found in Japan, Jordan, China, Iran, India, Turkey and Taiwan ethnic populations, when compared with the Saudi population.
Importantly, MAF of Saudi population was found significantly different from every population of the Caucasian group except for Greece population.The findings suggest that the susceptibility factor may behave differently in diverse populations and this fact needs to be considered when evaluating this genetic marker for risk, treatment or prognosis.The factors including racial difference, heterogeneity of the studied cohort and difference in sample sizes may be contributing to the difference in allele frequency of polymorphism.
The relative prevalence of the p53 Arg72 SNP in Asian and Caucasian subgroups also indicates population divergence and the interethnic differences, in addition to the elucidation of differential regulation of gene function among different populations.
The outcome of such studies may contribute to the development of the epidemiological database in Saudi Arabia helping in better clinical understanding and evaluation of enigmatic diseases like cancer.The allelic/ genotypes distribution data in healthy Saudi population in comparison to other populations can be used for the screening of individuals at risk or prone to developing cancer.The finding has contributed to the information about the relative prevalence of studied polymorphism and thus can lead to the use of this SNP as a biomarker along with a better understanding of cancer etiology in the Saudi population.CONCLUSION In conclusion, the allelic frequency distribution analysis of p53 exon4 Arg72Pro SNP in Saudi population showed significantly different prevalence in many populations in Asian subgroup and all but one populations in the Caucasian subgroup.However, the impact of this polymorphism influencing the cancer susceptibility or the prognosis in Saudi population needs future larger studies.

ACKNOWLEDGMENTS
The author thankfully acknowledges the Deanship of Scientific Research, Albaha University, Albaha, Saudi Arabia, for the software related support towards the conduct of the present study.

CONFLICT OF INTERESTS
The author declares no conflict of interests.

Table 1 .
Observed and expected genotypic frequencies of p53 Arg72Pro polymorphism in the control group

Table 2 .
Genotype and allele frequency distribution of p53 Arg72Pro gene variant in various populations of Asian ethnicity and p-values in comparison to Saudi Arabian population

Table 3 .
Genotype and allele frequency distribution of p53 Arg72Pro gene variant in various populations of Caucasian ethnicity and p-values in comparison to Saudi Arabian population