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ORIGINAL ARTICLE
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The mouse double minute 2 polymorphism is associated with both decreased p53 expression and poor clinicopathological outcomes of gastric cancer


 Translational Medicine Program, School of Surgery, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima, Thailand

Date of Submission05-Feb-2019
Date of Acceptance21-Jan-2020
Date of Web Publication23-Jul-2021

Correspondence Address:
Taweesak Tongtawee,
Translational Medicine Program, School of Surgery, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000
Thailand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_89_19

 > Abstract 


This study aimed to determine the mouse double minute 2 (MDM2) SNP309 polymorphism and to evaluate MDM2 and p53 expression and the association of MDM2 positivity in gastric cancer and clinicopathological outcomes. A total of 400 patients with chronic gastritis, precancerous lesions, and gastric cancer were used to identify the MDM2 SNP309 polymorphism by using the Taq Man SNP Genotyping assay. Immunohistochemistry was performed to evaluate MDM2 and p53 expression. The associations of polymorphisms, protein expression, clinicopathological outcomes, and gastric cancer risk were calculated by multivariate Cox proportional hazards regression model analysis and expressed by odds ratios (ORs) and 95% confidence intervals (CIs). The MDM2 SNP309 G/G homozygous polymorphism was significantly associated with expressed MDM2 in gastric cancer (OR = 1.57, 95% CI = 1.39–2.03, P = 0.039). Moreover, in gastric cancer, p53 was significantly decreased compared to MDM2 (P = 0.007). However, MDM2 and p53 expression were not significantly different among genotypes, and the G/G genotype can result in the altered protein expression of p53 in gastric cancer. Clinicopathological outcome was significantly associated with MDM2 expression, including tumor location in the upper gastric region (OR = 1.48, 95% CI = 1.25–3.54, P = 0.037), undifferentiated type (OR = 2.47, 95% CI = 1.38–4.14, P = 0.016), presence of lymphatic invasion (OR = 1.96, 95% CI = 1.22–3.19, P = 0.014), and unresectable tumor (OR = 3.39, 95% CI = 1.61–4.94, P = 0.017). Our study indicated associations of the MDM2 SNP309 G/G homozygous polymorphism, MDM2 and p53 expression. Therefore, G/G-associated MDM2 revealed that P53 expression was decreased in gastric cancer and poor clinicopathological outcomes. Understanding the genetic polymorphisms and expression of MDM2 may help explain gastric cancer risk.

Keywords: Gastric cancer, mouse double minute 2 expression, mouse double minute 2 SNP309, p53 expression, polymorphism



How to cite this URL:
Bartpho TS, Wattanawongdon W, Tongtawee T. The mouse double minute 2 polymorphism is associated with both decreased p53 expression and poor clinicopathological outcomes of gastric cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=307808




 > Introduction Top


Gastric cancer is one of the major causes of mortality and morbidity worldwide[1] and is the second leading cause of global cancer deaths.[2] Two-thirds of the incidences of gastric cancer worldwide occur in developing countries.[3] Approximately three-quarters of gastric cancers occur in Asia, with 80% of cases originating in Japan and China. In Thailand, gastric cancer is the sixth most common cancer in males and ninth in females. The annual incidence in Thailand is 5 cases/100,000 people[4] with incidence varying with geography. The northern region of Thailand has the highest incidence rate, whereas the southern region has the lowest rate.[5] Similar to other complex diseases, gastric carcinogenesis is a multifactorial process that requires alterations in the expression of oncogenes and tumour suppressor genes. This multistep process is caused by environmental factors that cause damage in the mucosa and inhibit cell repair.[6] In addition, a host of genetic factors plays a crucial role in these various transitional steps: normal mucosal/superficial gastritis, atrophic gastritis, and carcinoma transition.[7]

Mouse double minute 2 (MDM2) is an oncoprotein that acts as a negative regulator that inhibits p53 tumor suppressor activity; p53 acts on the stress response to cell cycle arrest, cellular senescence, and apoptosis.[8],[9] MDM2 directly binds to p53 and regulates its location, stability, and activity as a transcriptional activator.[10],[11] Thus, MDM2 plays an important role in carcinogenesis, with a polymorphism in the MDM2 promoter region (SNP309 T>G, rs2279744) having been found to increase the affinity of the transcriptional activator Sp1, which results in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway.[8],[12],[13] Levels of the MDM2 protein in a cell or organism appear to have a large effect on the p53 response and cancer formation. Interestingly, 7% of 3000 tumors screened from 28 different tumor types had MDM2 amplifications.[14] It has been proposed that high levels of MDM2 expression produce a weakened p53 tumor suppressor pathway in individuals with a wild-type p53 allele, resulting in a higher mutation rate, poorer DNA repair processes, and reduced apoptosis, leading to faster and more frequent tumor formation.[10] Surveys of cell lines and tissues with the SNP309 G/G homozygous genotype have shown at the RNA, and the protein levels were elevated in cells with SNP309. Clearly, cells with a SNP309 G/G homozygous polymorphism and a higher level of MDM2 protein had a lower apoptotic response than cells that were T/T at the SNP309 locus.[12],[15] Regarding cancer development, the SNP309 polymorphism of MDM2 appears to play a role in modulating the risk of the development of gastric carcinogenesis, such as the risk associated with the Chinese Han population.[2] The overall risk of gastric cancer was significantly increased with the polymorphism under a recessive model in a Japanese population,[13] but was not associated with an increased gastric cancer risk in a Korean population.[16] The impact of genetic effects on MDM2 protein expression on clinicopathological outcomes and gastric cancer risk has not yet been established in a Thai population.

The aim of this study was to determine the association between the host genetic factor of MDM2 SNP309 polymorphisms and MDM2 protein expression in patients with chronic gastritis, precancerous lesions, or gastric cancer in a cross-sectional study. This study also aimed to evaluate MDM2 and p53 expression and the association of MDM2 positivity in gastric cancer as well as clinicopathological outcomes.


 > Materials and Methods Top


Patients and specimens

A total of 400 patients underwent esophagogastroduodenoscopy (EGD) consisting of chronic gastritis, precancerous gastric lesions, and gastric cancer. The EGD procedure was performed using an upper gastrointestinal video endoscope (Olympus Evis Exera III, cv-190, Olympus Corp., Tokyo, Japan). The entire stomach was first examined with conventional endoscopy, and then the biopsy was performed using the “Site Specific Biopsy” technique.[17] Surgical resection was performed at the Suranaree University of Technology Hospital, the Buriram Hospital Medical Center, or the Surin Hospital Medical Center of northeast Thailand between January 2011 and December 2016. Histological analysis of tissue specimens with chronic gastritis, precancerous lesions, and gastric cancer were assessed and graded by 5 different pathologists. Written informed consent was obtained from all patients, and the study protocol was approved by the Ethics Committee for Research Involving Human Subjects, Suranaree University of Technology (EC-59-45 and EC 16-2560). The methods were carried out in accordance with good clinical practice and the guidelines of the Declaration of Helsinki. The patients were clinically evaluated according to the tumor-node-metastasis (TNM) staging for liver tumors developed by the American Joint Committee on Cancer (8th edition, 2018) for tumor stage, histologic grade, metastasis, fibrosis score, and overall survival (OS) rates.

DNA extraction

Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissues from 400 patients. Briefly, deparaffinization of the paraffin-embedded tissues was conducted using xylene and hydrated in 100% ethanol and then subsequently digested by lysis buffer and proteinase K according to the manufacturer's instructions (QIAamp DNA FFPE tissue kit, Qiagen, Dusseldorf, Germany). Genomic DNA was purified from the tissue lysate using the QIAamp spin column and eluted and stored at −20°C.

Mouse double minute 2 SNP309 polymorphism analysis

The polymorphism of MDM2 SNP309, rs2279744 (T>G), was determined by Taq Man allelic discrimination using the predesigned custom Taq Man SNP genotyping assay. Forward primers were used along with the wild-type probe HEX, and reverse primers FAM were used for variant alleles. Primers and probes were supplied by Applied Biosystems (Foster City, CA, USA). The probes of fast start DNA master hybridization probes (20 M each) were used (Roche Diagnostics, Neuilly-sur-Seine, France). Real-time polymerase chain reaction amplification comprised an initial denaturation at 95°C for 10 min, followed by 55 amplification cycles (with a temperature transition rate of 2.2°C/s), degeneration at 92°C for 30 s, annealing at 42°C for 45 s, and extension at 72°C for 5 s (with a temperature transition rate of 4.4°C/s). The genotype of each patient was categorized into 1 of 3 genotypes, SNP309 G/G homozygous, T/T homozygous, and G/T heterozygous. Negative controls and duplicate samples used for the accuracy of genotyping and SNP data were analysed with LightCycler® 480 software 1.5 (Roche Diagnostics, Neuilly-sur-Seine, France).

Mouse double minute 2 and p53 protein detection

Immunohistochemistry (IHC) was performed to detect MDM2 and p53 protein expression in tissue samples. Briefly, slides were prepared from sections of paraffin-embedded tissue samples. Sections were cut 4–5 μm thick. First, the sections were deparaffinized in xylene, rehydrated in a graded ethanol series (70%, 95% and 100%) and washed in distilled water. The sections were microwaved for 5 min in 10 mM citrate buffer (pH = 6.0) for antigen retrieval. After the sections were cooled at room temperature, they were incubated with 1.5% normal blocking serum for 1 h, followed by incubation with primary antibody (anti-MDM2 or anti-p53 antibody), monoclonal mouse antibody (dilution 1:100, clone SMP; Santa Cruz Biotechnology, Santa Cruz, CA, USA) overnight at 4°C. The slides were rinsed and incubated with the biotinylated goat anti-mouse secondary antibody (1 μg/ml) for 30 min at room temperature, followed by incubation with horseradish peroxidase-conjugated avidin–biotin complex (Thermo Fisher, Hanover Park, Illinois, USA) for 30 min at room temperature. The specific binding of antibodies within the tissue sections was visualized with an aminoethyl carbazole substrate solution (Life Technologies Corp., Carlsbad, California, USA), and counterstaining was conducted.

Mouse double minute 2 and p53 immunohistochemical staining evaluation

IHC analysis of MDM2 and p53 were evaluated by 5 independent pathologists. They were blinded to the patient's clinicopathological data. The percentage of MDM2- or p53-positive cells stained was scored as follows: Lack of staining was scored as 0 (negative), 1 (1%–10%), 2 (11%–50%) and 3 (>51%). The cases classified as 0 were considered as protein-negative expression, whereas 1+, 2+, and 3+ were established as protein-positive expression.

Statistical analysis

Comparisons between patient groups were conducted using analysis of variance for the patient's demographical data. The statistical significance of any associations between MDM2 polymorphisms and MDM2 protein expression and the clinicopathological outcomes of gastric cancer were evaluated using univariate Cox regression model analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by multivariate Cox proportional hazards regression modeling. The differential expression between MDM2 and p53 was analyzed by Student's t-test. P < 0.05 was considered as statistically significant. All statistical analyses were carried out using SPSS for Windows (version 20.0; IBM Corp., Armonk, NY, USA).


 > Results Top


Patient characteristics and gastric mucosal pathology

The number of patients with chronic gastritis, precancerous lesions, and gastric cancer were 125, 113, and 162, respectively. Patient age was not significantly different among different gastric mucosal pathologies (mean ± standard deviation: chronic gastritis = 55.03 ± 12.96, precancerous lesions = 54.32 ± 15.83, and gastric cancer = 61.38 ± 12.39). The number of male patients with chronic gastritis, precancerous gastric lesions, and gastric cancer were 45 (36%), 45 (39.8%), and 117 (72.2%), respectively. There was no significant difference in gender, as males with gastric cancer were the most frequent (72.2%).

Mouse double minute 2 SNP309 polymorphism associated with mouse double minute 2 expression

Of the 400 patients, MDM2 protein expression was detected in 85/125 of patients with chronic gastritis (68%), 61/113 with precancerous lesions (58.1%), and 105/162 with gastric cancer (64.81%). Expression of p53 was detected in 120/125 of patients with chronic gastritis (96%), 109/113 with precancerous lesions (96.46%), and 156/162 with gastric cancer (96.30%). There was no statistically significant difference between the expression of MDM2 or p53 among the gastric mucosal pathology groups [Table 1]. MDM2 or p53 was expressed in the cytoplasm and nuclei [Figure 1].
Table 1: Patient's demographics data among gastric mucosal pathology

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Figure 1: Representative photomicrograph of immunohistochemistry of mouse double minute 2 expression on gastritis tissues. (a) Mouse double minute 2-negative cells stained, (b) mouse double minute 2-positive cells stained in gastric cancer (×200), (c) P53-positive cells stained in gastric cancer (×200)

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We performed analyses of the association of MDM2 SNP309 polymorphisms and MDM2 protein expression among different gastric mucosal pathologies. Patients with T/T homozygous and T/G heterozygous genotypes displayed tissues that were not significantly associated with MDM2 expression in chronic gastritis, precancerous lesions, or gastric cancer. Interestingly, the G/G homozygous genotype group was significantly associated with MDM2-positive expression with increased risk (OR = 1.54, 95% CI = 1.39–2.03, P = 0.039) in gastric cancer, according to the univariate analysis [Table 2], and (OR = 1.57, 95% CI = 1.14–3.49, P = 0.039) according to the multivariate analysis [Table 3].
Table 2: Mouse double min 2 polymorphism related to mouse double min 2 expression and gastric mucosal pathology (univariate cox regression model analysis)

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Table 3: The association of mouse double min 2 expression and clinicopathological outcome of gastric cancer (univariate cox regression model analysis)

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The expression of mouse double minute 2 affects p53 expression in gastric cancer

The specific expression of MDM2 and p53 was determined in gastric cancer. MDM2-or p53-positive cells were scored. A score of 3 (>51%) indicated that the protein was highly expressed. Because the MDM2 protein mainly suppresses the p53 protein, we determined the effect of MDM2 expression on p53 expression by comparing the percentage of highly expressed MDM2 and p53 in precancerous lesions and gastric cancer [Figure 2]. Our results showed that 60.66% of the total number of MDM2-positive cells highly expressed MDM2 and 68.81% of the total number of p53-positive cells highly expressed p53 in precancerous lesions, while 60% of the total number of MDM2-positive cells highly expressed MDM2, but 43% of the total number of p53-positive cells highly expressed p53 in gastric cancer [Figure 2]. We found that p53 was significantly decreased compared to MDM2 in gastric cancer (P = 0.007). These results suggest that MDM2 can affect p53 expression and that this mechanism may additionally affect p53 expression in gastric cancer than in precancerous lesions.
Figure 2: P53 expression upon highly mouse double minute 2 protein expression in precancerous or gastric cancer

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G/G genotype of SNP309 mouse double minute 2 polymorphism affect p53 expression in gastric cancer

We compared the frequencies of genotypes of MDM2 SNP309, T/T, T/G, and G/G in gastric cancer patients with highly expressed MDM2 and p53. The percentage of highly expressed MDM2 showed 47.52%, 36.20%, and 54.10% in genotype T/T, T/G, and G/G, respectively. In contrast, the percentage of highly expressed p53 was 52.56%, 54.49% and 46.79% in genotypes T/T, T/G and G/G, respectively [Figure 3]. Although MDM2 and p53 expression were not significantly different among genotypes, the G/G genotype can result in altered protein expression of p53 in gastric cancer patients. Therefore, the G/G-associated MDM2 polymorphism revealed that p53 expression was decreased in gastric cancer.
Figure 3: Mouse double minute 2 and P53 expression in gastric cancer of SNP309 mouse double minute 2 polymorphism

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Clinicopathological data and risk of mouse double minute 2 expression in gastric cancer

The clinicopathological data and univariate analysis are summarized in [Table 3]. Differentiated types of gastric cancer, absence of lymphatic invasion, microscopic residual tumours, and 5-year survival were negatively associated with MDM2 expression (P = 0.042, P = 0.029, P = 0.028, and P = 0.039, respectively). In contrast, upper gastric tumor, undifferentiated type, presence of lymphatic invasion, TNM Stage IV, and unresectable tumor were positively associated with MDM2 expression (P = 0.029, P = 0.028, P = 0.019, P = 0.042, and P = 0.012, respectively). Other clinicopathological characteristics such as tumor size, vascular invasion, pathological T stage, and carcinoembryonic antigen were not associated with MDM2 expression.

The multivariate analysis incorporated all relevant clinicopathologic features such as age, gender, underlying disease, and family history of gastric cancer [Table 4]. The clinicopathological data of gastric cancer patients were significantly associated with an increased risk of MDM2 expression, such as upper gastric tumor (OR = 1.48, 95% CI = 1.25–3.54, P = 0.037), undifferentiated type (OR = 2.47, 95% CI = 1.38–4.14, P = 0.016), presence of lymphatic invasion (OR = 1.96, 95% CI = 1.22–3.19, P = 0.041), and unresectable tumor (OR = 3.39, 95% CI = 1.61–4.94, P = 0.017). However, the absence of lymphatic invasion and microscopic residual disease were negatively associated with MDM2 expression (P = 0.031 and P = 0.026, respectively), while differentiated type, TNM Stage IV, and 5-year OS were not associated with MDM2 expression.
Table 4: The association of the clinic pathological outcome of gastric cancer and mouse double min 2 protein expression (multivariate cox proportional hazards regression model analysis)

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 > Discussion Top


This study found that the MDM2 SNP309 polymorphism is associated with MDM2 protein expression. As with previous studies, the MDM2 SNP309 G/G homozygous polymorphism was associated with an increased risk of gastric carcinoma.[13],[18] In this study, the MDM2 SNP309 G/G homozygous polymorphism was found in 45% of the Thai gastric cancer patients. The G/G homozygous polymorphism was associated with MDM2 expression in gastric cancer. In addition, we found highly increased MDM2 expression in gastric cancer compared to precancerous lesions. Increased MDM2 expression in gastric cancer was significantly different with reduced p53 expression (P = 0.007). These results suggest that MDM2 can affect p53 expression by decreasing p53 expression in gastric cancer or may promote the attenuation of the p53 pathway, thus contributing to gastric cancer. This result revealed that the G/G-associated MDM2 SNP309 polymorphism can contribute to the reduction of p53 expression in gastric cancer.

We further investigated the association of MDM2 expression and clinicopathological features in gastric cancer patients. We found that MDM2 expression was associated with clinicopathological features, such as tumors located in the upper gastric region, undifferentiated types, presence of a lymphatic invasion, and unresectable tumors. These results indicated that MDM2 is associated with the clinical progression of gastric cancer. Moreover, MDM2-positive expression revealed that patients with a G/G homozygous polymorphism showed a 1.57-fold increase in gastric cancer risk [Table 4]. Chronic gastritis and precancerous lesions also showed a higher number of MDM2-positive cells in patients with the G/G homozygous polymorphism compared to those with T/T or T/G alleles, but these patients did not show a significantly increased risk of gastric cancer, indicating that T carriers do not affect tumourigenesis [Table 2]. This study was consistent with previous results showing that G/G homozygous polymorphisms increase the risk of tumourigenesis, severe atrophic gastritis, and intestinal-type carcinoma, but this outcome did not affect susceptibility to gastric atrophy.[13] Recently, the MDM2 SNP309 G/G homozygous genotype has been shown to be a risk factor for gastric cancer in Thai patients.[19] Furthermore, MDM2 SNP309 G/G homozygous polymorphisms are associated with severe inflammation in Helicobactor pylori-associated gastritis.[20],[21] It is postulated that the MDM2 polymorphism affects protein expression and is potentially associated with the development of gastric carcinoma in Thai patients. Since the MDM2 SNP309 polymorphism was discovered, it has been shown to be associated with an increased risk of tumor formation. In addition, a combination of the G/G genotype can elevate MDM2 levels and severely compromise the p53 tumor suppressor pathway, possibly resulting in a higher mutation rate, poorer DNA repair processes and reduced apoptosis, which may lead to faster tumor formation. Our results showed that the clinicopathological features of gastric cancer indicated a statistically significant association between MDM2 expression and gastric cancer risk. Clinicopathological features, such as tumor location, tumor histological type, lymphatic invasion status, TNM stage, tumor residual status, and 5-year OS, were significantly associated with MDM2 expression. Moreover, severe clinicopathological outcomes were associated with MDM2-positive expression, including the undifferentiated type, presence of lymphatic invasion, TNM Stage IV, and unresectable tumor. It is possible that these clinicopathological features are associated with the loss of p53 expression, which is inhibited by MDM2 expression. Patients with differentiated histological types, absence of lymphatic invasion, microscopic residual tumors, and MDM2-negative expression had significantly better than patients with positive MDM2 expression [Table 3]. Moreover, patients with MDM2-positive expression and undifferentiated type or unresectable tumor had a 2.47-fold and 3.39-fold increase in gastric cancer risk, respectively [Table 4]. This finding supports the hypothesis that an MDM2 SNP309 polymorphism and increased MDM2 expression are associated with an attenuation of the p53 pathway and an increased risk for gastric cancer, which is consistent with previous studies.[19],[22],[23],[24],[25],[26],[27] With respect to prognosis, gastric cancer patients had MDM2 expression levels up to 64.81%. In addition, there was no association between 5-year OS and MDM2 expression. The 5-year OS in the 149 patients with MDM2-negative expression was 65.77% [Table 3]. These results indicated that MDM2 was an independent marker of poor prognosis for gastric carcinoma. However, other studies have attempted to predict prognosis using the MDM2 SNP309 polymorphism and protein expression.[13],[19],[26],[28] In the future, further studies of MDM2 expression in combination with other oncoproteins, tumor suppressor proteins, and markers could be helpful. However, this study had some limitations. This was a multicenter study in northeast Thailand. To verify the results, a larger sample size is needed in future studies, and population-based prospective studies are needed for more rigorous analyses of subgroups in terms of genotype–environment interactions.


 > Conclusions Top


Our study indicated that there were associations in the MDM2 SNP309 G/G homozygous polymorphism, MDM2 protein expression, and clinicopathological outcomes that may explain gastric cancer risk in a Thai population. There is promise that understanding MDM2 polymorphisms and protein-inducible expression in patients might help prevent and treat gastric cancer. Specifically, MDM2 expression and polymorphisms may provide better outcome predictions and the optimal selection of therapeutic agents.

Financial support and sponsorship

This research was supported by a grant from Suranaree University of Technology and by office of the higher education commission under NRU project of Thailand.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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