Most of the human cancers begin at the level of genetic mechanisms where normal cell cycle is disrupted or abnormal replications of genetic material go unchecked. Either the increased level of cellular proliferation or decreased level of apoptotic pathway will interrupt the homeostasis of cells and engender the niche for potential tumorigenesis. Attributed as a guardian of the genome, p53 protein is well recognized in suppressing tumour development as in cell cycle control, apoptotic pathway, and DNA repair mechanism. Functioning as a tumour suppressor protein, the level of p53 is tightly controlled by MDM2 protein. The p53 dependent mechanism of MDM2 protein regulates p53-mediated transcriptional activity in two ways, firstly MDM2 protein binds to p53 transcriptional activation domain(TAD) making it transcriptionally inactive and secondly degradation of p53 in the cytoplasm by acting as an E3 ubiquitin ligase. MDM2 gene expression is in turn controlled by active p53 protein through a p53 responsive promoter(P2) located in first intron of this gene. Thus, MDM2-p53 autoregulatory loop forms a finely balanced regulatory network and if it is disrupted, the balances of the proteins are out and the cells become more susceptible to cancer. Following exposure of extracellular and intracellular stimuli that causes DNA damage such as ionizing radiation, DNA damage, hypoxia, infectious viruses, p53 protein is stabilized in the nucleus and its association with MDM2 is disrupted by either post-translational modifications of proteins or interference of MDM2 function by p19ARF. In this way, elevated level of p53 proteins activate the genes possessing p53 responsive elements and carried out its function.
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MDM2 has not only p53 dependent functions but it also has some p53 independent functions which are also critical for carcinogenesis. MDM2 protein can directly bind with pRb protein and E2F1(E2F transcriptional factor 1) promoting G1 to S phase progression of the cells through interrupting pRb as well as stimulating E2F1 functions. In response to DNA damage, p21 protein which is a cyclin dependent kinase inhibitor is up-regulated resulting in G1 phase cell cycle arrest. MDM2 can also act as a negative regulator for p21 protein by promoting its proteasomal degradation in the nucleus via p53 independent pathway. Furthermore, MDM2 protein is an essential attribute for ubiquitylation and degradation of certain steroid hormone receptors known as glucocorticoid receptor, androgen receptoron the other hand it can enhance the estrogen dependent transcription through estrogen receptor Î±(ERÎ±).
MDMX/MDM4, a structurally similar protein with MDM2 especially in the N-terminal p53 binding domain and C-terminal domain, is a well-known MDM2 family member. MDMX/MDM4 protein binds to transactivation domain of p53 protein and interfere its function. Furthermore, MDMX/MDM4 protein can also bind with MDM2 protein through ring finger domain in C terminus region and upon this hetero-oligomerization, the stability of MDM2 is substantially increased. On the other hand, there is a conflicting fact about MDMX that it does not have nucleocytoplasmic shuttling function thereby hindering MDM2 mediated p53 protein degradation by creating a nuclear pool.
Knockout mice of MDM2 gene are lethal in their developmental stage due to p53 dependent excessive apoptosis but double knockout mice for both MDM2 and p53 survive which shows the strong evidence for MDM2 regulation of p53 stability in vivo. Knockout mice of MDMX/MDM4 gene can also lethal in embryonic stage whereas the defect is in proliferation but not apoptosis as in MDM2 gene. Recent discovery of single nucleotide polymorphism(SNP) at 309th position in MDM2 gene promoter sheds a new light on how SNP309 could play a role in contributing to the development of cancers. The relationship between SNP309 in MDM2 gene promoter and potential tumour development will be thoroughly discussed in this review and table1, 2.
Since SNP 309 is a naturally occurring polymorphism, not a mutation, it can be commonly found in general population. By using 300 base pairs from genomic DNAs isolated from 50 healthy volunteers, SNPs have been detected in two positions, at nucleotide 309th and at 344th in MDM2 promoter. SNP 344 is a change of nucleotide from T to A and it is rarely seen among general population which is only 8 % for heterozygous state therefore no further studies are done. Whereas, SNP309 polymorphism is a T to G variation at the 309th nucleotide in the first intron of the intronic promoter of MDM2 gene and it has relatively high frequency, 40 % for heterozygous state T/G and 12 % for homozygous G/G.
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The presence of SNP309 in the promoter of MDM2 gene extends the length of one of the putative DNA binding sites for the transcriptional activator namely stimulatory protein 1(Sp1) and also increases the binding affinity of it. Sp1 is a co-activator of various hormone receptors including ER and it contains estrogen response element(ERE) in its locus so it is known to be one of the participants in estrogen mediated gene transcription. Therefore, SNP309 in MDM2 gene promoter may alter the effects of hormones such as estrogen in human neoplasm. The levels of MDM2 RNA and protein become higher and subsequent attenuation of p53 protein and cancer formation can be seen(Figure 1 and 2). Overexpression of MDM2 protein leads to functional inactivation of wild-type p53 protein causing higher incidence for earlier age of onset, increased risk and poor survival of both hereditary and sporadic cancers in different tissues.
The frequencies of MDM2 SNP309 are varied depending on the race and ethnics. Recent studies described that G allele was assumed to be descended from the Caucasians to African Americans due to migrations of human out of Africa and admixture with Caucasians, thus the frequency of G allele seemed to be higher in Caucasians. Selective pressure on SNPs in p53 gene could be possible because p53 takes part in tumour suppression, embryonic development and even responds to inflammations, thus infections may also play a role in this selection.
The different frequencies for other ethnics are also discussed in many studies and noted that the percentage of SNP309 G allele was higher in Ashkenazi Jewish whereas it is lower in Caucasians. One study stated that in Asian population, the frequency for G allele was elevated than that of Caucasians. Since allele frequencies are different among ethnics, races and population, the confounding result could be seen if the numbers of patients from one ethnic group are dominant over other counterparts in the sample being studied.
From this information, we can hypothesize that Ashkenazi Jewish and Asian have the highest percentage of SNP309 G allele. Therefore, these two ethnic groups might have more significant cancerous changes in association with SNP309 G allele than those with other population. For these reasons, it is important to consider the race and ethnic group in each study and crucial to compare the same race and ethnic population to get more accurate outcomes.
Researchers cannot exclude the effect of SNP309 G allele alone on various types of cancer by analyzing the association with carcinogenesis. Associated factors, for example, TP53 mutation, steroid receptor status, environmental stress (smoking, dietary carcinogen, chronic viral infection), gender status, race & ethnicity, functional polymorphisms in p53-MDM2 related genes and other genetic predispositions also have to be considered. It was shown in many studies that these associated factors play a significant role in time of tumour onset. "Age-specific incidence of cancer is dependent on the number of rate-limiting mutations required for a given cancer, the mutation rate per mitosis and the net proliferation rate of the effected cells". p53 gene has an influence on all three factors and inhibition of the p53 pathway by SNP309 could affect all three factors and leads to acceleration of tumour formation. In this way, SNP309 acts as a rate limiting factor in tumorigenesis. In this review, the relationship between SNP309 and different types of cancers based on their associated factors will be discussed.
An autosomal dominant cancer predisposing syndrome named Li-Fraumeni syndrome (LFS) is commonly associated with p53 germline mutation and is characterized by occurrence of heterogeneous types of tumors at young age. The presence of SNP309 G allele in LFS patients has a distinct influential effect on earlier onset of tumour appearance. In one study, from 41 unrelated LFS families, 61 patients who have p53 germline mutation were collected to examine the effect of SNP309. Suprisingly, G allele carriers (T/G or G/G) were approximately 10 years earlier age of tumour onset than homozygous T allele carrier (T/T) patients. This result reveals the fact that G allele of SNP309 behave as a genetically modifying factor in TP53 mutant patients. There is also another interesting point that the polymorphism identified in coding region of p53 gene had an associated issue with SNP309. G allele of SNP309 and Arg allele of p53 codon72 polymorphism had a combination effect on this tumorigenesis.
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In one report, the finding showed that SNP309 G allele had an earlier age of onset for tumour with p53 germline mutation carriers than those with T allele carriers, on the other hand, in the case of TP53 negative LFS and LFS related patients; the difference for age of tumour onset was insignificant between G allele and T allele groups. Therefore, SNP309 may not act as an accelerating factor for TP53 negative LFS patients and the result for earlier age of onset for p53 mutation carrier is consistent with that of Bougerad et al., 2005.
One report studied with 88 individuals from LFS families who carry germline p53 mutation in one allele and the outcome indicated that the earlier onset of tumour can be found in both homozygous (G/G) and heterozygous (T/G) SNP309 carriers.In LFS criteria, multiple primary tumors can develop throughout the life time. The most frequent tumors can be found in these patients are soft tissues sarcomas, breast cancer and osteosarcomas. In patients with either heterozygous or homozygous G allele of SNP309, the incidence of multiple tumour appeared in a life time was significantly more than those with T/T genotype. From these results, SNP309 has an impact on the two critical points of LFS, namely the age of tumour onset and the manifestation of multiple tumors in life. Although SNP309 seems to play a role in age of onset of tumours with p53 germline mutation only, it is also involved in other cancers without p53 mutation. This type of cancer lacking p53 mutation is observed in sporadic cancers and proved in sporadic soft tissue tumour (STS) patients by Bond et al.
Overall, SNP309 influences the age of tumour onset with p53 germline mutation carrier patients(hereditary) and it may also have an effect on those without this mutation(sporadic).
In breast cancer, estrogens play a major role in cell growth and proliferation whereas glucocorticoids exert opposite action. Overexpression of MDM2 caused by variant SNP309 G allele works together with these steroid hormone receptors in enhancing tumorigenesis. MDM2 mediates glucocorticoid receptor(GR) degradation through ubiquitylation. In ER positive cells, the rate of carcinogenesis is significantly high compared to those with ER negative because estrogen can enhance MDM2 transcription by recruiting ER to MDM2 promoter in E2 dependent manner. Moreover, MDM2 can also physically interact with ER and activate estrogen dependent transcription. For these reasons, the patients who have both SNP309 G allele and ER positive become increased risk, earlier age of tumour onset and poor prognosis than others.
Recently, analysis on 658 Caucasians, Ashkenazi Jewish ethnic women with sporadic invasive ductal breast carcinoma(IDC) elucidated that women with high ER level who had G/G genotype were 7 years earlier age of onset than those with T/T genotype , on the contrary, women with low ER level had no obvious differences between G and T allele. Besides, the average age of tumour onset for most of the women was below 51 years(before menopause) when the level of estrogen became the highest level and the frequency of G allele was also higher in those premenopausal women than postmenopausal ones. To confirm this, another independent study was done with sample size 258 Caucasian women, not selected for Ashkenazi Jewish ethnic and the findings were the same.
The possible link between breast cancer with BRCA1/2 carriers and SNP309 is another interesting issue and there are a variety of inconsistent findings on that. Yarden et al, 2008 stated that SNP309 G allele serve as a modifier and accelerator of breast cancer in patients with mutant BRCA1/2 gene. On the other hand, the outcome another study with British population showed that in BRCA1 carriers, there was no association with either acceleration or incidence and this polymorphism.
In addition, SNP309 appears to affect the risk, age of onset for breast cancer diversely in heterogeneous population. Sun et al analysed a Taiwanese population and observed that both risk of tumour incidence and age of onset were increased in homozygous(G/G) genotype carrier women. One experiment with Chinese population showed that there was no significant association between SNP309 G allele and breast cancer(Ma et al., 2006). The risk of occurring breast cancer in both Whites and African-Americans was not observed but the cancer occurring age was earlier in those patients with p53 mutation. In British inhabitants, evidences for early age of onset of G allele carriers could not detected. The risk of cancer for SNP309 was examined in Turkish residence and also no association was found. Moreover, one study with German population found that not only the risk but also age of onset for breast cancer was unrelated with the polymorphism of SNP309.
To conclude, G allele of SNP309 in MDM2 gene promoter and steroid receptors signalling has a strong relationship in predisposing to cancer. SNP309 polymorphism alone cannot have much impact on breast cancer and other additional genetic variants are also essential to get the dominant outcome. Besides, these inconsistent findings may also be due to different ethnic groups of studies and their different environmental backgrounds.
In CRC, SNP309 G allele also takes part an interesting role in predisposing tumour. SNP309 with p53 wild-type(WT) gives rise to earlier age of tumour onset but not for those with p53 mutant. This was confirmed with total 153 Italian white CRC patients, among them 77 patients were with wild-type p53 and 76 with mutant p53. In WT p53 group, patients with G/G variant were almost 10 years earlier in age of onset than their counterparts T/T genotype. In contrast, mutant p53 group didn't show any notable difference in age of onset between G/G and T/T genotypes. These findings can be reliable because mutant p53 itself can lead to cancer and the consequence of SNP309 G allele is masked when it is together with p53 mutation, on the contrary, when p53 status is wild-typed, the effect of SNP309 becomes relatively visible.
Most of the studies remarkably showed that some factors are concerned with SNP309 in carcinogenesis. One research evaluated that oestrogen played a part together with SNP309 G allele in tumour acceleration. In 165 Italian patients, of which 98 male and 67 female with CRC were tested. Then, it was found that the frequency of G allele was enriched specifically in women not in men. The data showed that in men, there was no distinct variation in age of onset between T and G allele. But in female patients, independent of the G allele status (homozygous or heterozygous), age of onset was obviously earlier about 9 year average than T allele and despite the status of p53 (wild-type or unknown), the dominant effect on female was consistent.
Another paper also strongly proved that in Finnish CRC patients, women bearing SNP309 G allele were slightly earlier in age of tumour onset than those with men. However, one paper stated that SNP309 G allele did not have a dominant effect on age of onset of CRC in both sexes. Although there are some contradictory issues upon age of onset among genders, the effect of SNP309 alone cannot be excluded and estrogen may confer as a modifying factor of SNP309 as in breast cancer.
To summarize the overall facts, SNP309 may be a modifier for age of onset in CRC especially in female gender and those with WT p53. But the correlation between the risk, incidence, recurrence of CRC in patients and SNP309 G allele cannot be verified. For these reasons, SNP309 may act as a low penetrance susceptibility tumour marker in CRC.
Unlike other tumours, it is critical to take into account the histology of tissue origin in lung cancer. Depending on the histology, the response and outcome of tumour can be different so tissue specific nature of SNP309 polymorphism plays a vital role. The correlation between SNP309 and lung cancer based on different races, smoking status, gender, age of patient and histology types were extensively studied.
In one study, 1,106 Chinese patients were divided into three groups according to the histological types, 476 with squamous cell carcinoma(SCC), 361 with adenocarcinoma(AC) and 269 with other cell types namely undifferentiated cancer, bronchioalveolar carcinoma and mixed cell carcinoma. It was supposed that SNP309 G allele was interconnected with risk of lung cancer in all cell types compared to that of wild-type T allele. In addition, there was some evidence that SNP309 polymorphism had an association with other p53 polymorphism. Whether the patients had G/G genotype or p53 Arg72Pro polymorphism (Pro/Pro genotype), there was a risk of occurring tumour and the risk was even higher if the patients had both polymorphisms. However, there was no linkage between increased risk of cancer and Arg/Arg genotype because Arg/Arg genotype had more effective apoptotic function and it could proficiently hinder the transformation of the cells. Besides, the proof for the interaction between smoking and SNP309 G allele was significant.
In addition, the risk of cancer susceptibility of non-small cell lung cancer was well-studied with Norwegian population. Analysis for risk of cancer was higher in G allele individuals than those with T allele and this effect was even more prominent in women because estrogen signalling has an impact on MDM2 expression. This result of having association between the risk and SNP309 G allele is tantamount to the hypothesis of Zhang et al although the ethnics and histological cell types of tumour are totally diverse.
Moreover, in Korean population, the risk of lung cancer and SNP309 G allele were also correlated. Various histology types named SCC, AC, small cell carcinoma and large cell carcinoma were studied. The findings showed that the G allele was apparently connected with risk of AC and subsequently the more G allele in patients, the greater the risk of AC. However, in the finding of Zhang et al, the risk was equal in all different histological cell types.
Recent paper suggested that SNP309 G allele and risk of cancer had no interconnection by using two ethnic groups, African-American and Caucasians. Besides, it was suggested that both gender and smoking were not associated with SNP309 polymorphism. Moreover, the findings from one study postulated that in Chinese patients, there was no associated effect for SNP309 G allele and risk of cancer. Interestingly, this result was inconsistent with the findings of Zhang et al whose experimental population was also Chinese.
In contrast, SNP309 G allele has been recently identified as having a protective effect on the risk of lung cancer. It was studied with non-Hispanic white population and observed that wild-type T allele caused increasing the risk and the reasons for these contradictory results may be because of different tissue histology, ethnic, genetic background and genetic susceptibility of individual patients to lung cancer. Furthermore, the associated factors considered in each paper are also non-identical.
Some researchers argued that SNP309 G allele has no effect on the risk of cancers. The role of SNP309 polymorphism in regard to cancer development becomes more unconvincing than finding an answer. The fact that there was no correlation between SNP309 polymorphism and the risk of cancer was proved by Pine et al in African-American ethnic. While Zheng et al stated the involvement of SNP309 G allele in Chinese patients, another study on Chinese cancer patients by Hu et al proved otherwise. Whereas some studies demonstrated that G allele has a role in facilitating the development of cancers, others showed that G allele have a rather unorthodox protective effect on the risk of lung cancer in comparison with wild-type T allele. Due to the presence of different ethnic groups, genetic backgrounds and individual susceptibility to lung cancers being prevalent on each study, they all account for diverse findings in regard to SNP309 polymorphism in lung cancer risk.
To sum up, SNP309 G allele is predisposing the risk of cancer formation and its effects may be varied according to the histological subtypes. In addition, it has synergistic effect on acceleration of cancer with the p53 polymorphism. From primitive knowledge, smoking is a well-known carcinogens and it can cause lung cancer especially in male. Yet, the estrogen receptor is participated in regulation of MDM2 expression and enhanced the attenuation of p53 pathway. Therefore, the gender difference in lung cancer may exist.
HCC is one of the most prevalence cancers in Asian and major risk factors are alcohol, aflatoxin, viral infection namely hepatitis B virus(HBV) and hepatitis C virus(HCV). Besides, some reports stated that the polymorphisms in the interleukin-1Î² as well as UDP glucuronosyltransferase 1A7 genes take part in the development of HCC. Therefore, researchers are curious to investigate SNP309 polymorphism present in the MDM2 gene promoter and its association of HCC.
In recent studies, SNP309 G allele was strongly modified the risk of HCC patients who have underlying viral hepatitis infection. Experiment with 435 Japanese patients who had chronic HCV infection revealed that the ratio of G allele was higher than T allele and G allele had an influential effect on risk of causing HCC patients with HCV infection but not on the age of onset for tumour. In addition, the relation between G allele and alcohol could not find because the allele frequency was same whether the patients had cirrhosis or not. Thus, the hypothesis can be drawn that SNP309 polymorphism is not strongly associated with cirrhosis in Japanese and further researches are required to deduce a better verification.
Most of the studies were consistent with each other and showed that SNP309 G allele gave rise to acceleration of cancer in patients with underlying infection either HBV or HCV. Furthermore, one research paper proposed that there might be an association between G/G genotype SNP309 and p53 Arg72Pro polymorphism.
From these data, we can conclude that SNP309 G allele alone may not stimulate HCC formation and it only facilitates tumorigenesis with the ones who have underlying infection. Furthermore, most studies of MDM2 polymorphism and HCC are done in Asian population so it is necessary to study in diverse population with large sample size to get better understanding the effect of SBP309.
The predisposition of SNP309 G allele on oesophageal cancer is also curious to know and both environmental risk factors and underlying genetic background play a role in this tumorigenesis. The very first research paper was done with 758 Han Chinese patients and 1,420 control people, the results proposed that patients carrying G/G genotype had a higher risk for the development of cancer than T/T genotype carriers. However, the heterozygous carriers(T/G) were not associated with the risk of cancer so it could be assumed that G allele has a recessive effect on this carcinogenesis. Moreover, SNP309 polymorphism had a multiplicative effect with p53 Arg72Pro polymorphism and with smoking as well. Among smokers, the odd ratio was 2 to 3 times higher for those with both G/G and Pro/Pro genotypes than those with either one of them.
Overall, SNP309 G allele may have a predisposing effect on carcinogenesis of oesophagus. As far as to this date, Hong et al paper is the primordial and only paper on studying the association between these two and many studies on multiracial ethnic with large sample size are extensively required to draw the conclusion.
Like other cancers, SNP309 polymorphism may be correlated with one of the haematological disorders, leukaemia, in term of incidence, onset of tumour, treatment outcome and prognosis on discrepant ethnics. In acute lymphoblastic leukaemia(ALL) patients, the impact of MDM2 polymorphism was varied according to the different populations. The earlier age of onset for variant G allele could be noted in Caucasians and Black groups whereas in Hispanic population showed no difference.
Recently, in Chinese population, the G allele could neither affect on the age of onset nor survival but even reduced the risk of acute myeloid leukaemia(AML) and acute lymphoid leukaemia(ALL) which was incompatible with other results. Moreover, G allele acted as a dominant allele which means that either heterozygous(T/G) or homozygous(G/G) decreased the risk in both male and female patients. Additionally, SNP309 G allele did not have gene to gene interaction with other p53 polymorphism in this tumour.
However, the association of this polymorphism and leukaemiogenesis could be observed neither for age of onset nor for incidence in B typed chronic lymphoblastic leukaemia(CLL) though the obvious result of decreased overall survival in patients was found. Yet in German society, SNP309 polymorphism had no predisposition to both age of onset and outcome of CLL.
Therefore, in leukaemia, the findings are irreconcilable with each other and the association with SNP309 may be conflicting due to different ethnics in each research and the gender bias cannot be seen.
For gastric cancer, 410 Japanese patients were extensively studied and found that the SNP309 G/G genotype was related with increased risk for sporadic cancer patients who had p53 mutation. G allele had more prone to appear extra gastric tumour than T allele but the age of tumour onset between these two alleles was similar. This study also showed that the poor prognosis was concerned with SNP309 G/G genotype.