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ORIGINAL ARTICLE
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RAD51 135G>C polymorphism in esophageal cancer and meta-analysis in gastrointestinal tract cancers


1 Department of Human Genetics, Human Cytogenetics Laboratory, Guru Nanak Dev University, Amritsar, Punjab, India
2 Department of Surgery, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
3 Department of Pathology, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
4 Department of Radiotherapy, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India

Date of Submission12-Jul-2020
Date of Decision29-Aug-2020
Date of Acceptance30-Sep-2020
Date of Web Publication23-Oct-2021

Correspondence Address:
Vasudha Sambyal,
Department of Human Genetics, Human Cytogenetics Laboratory, Guru Nanak Dev University, Amritsar, Punjab
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_784_20

 > Abstract 


Background: A functional single-nucleotide polymorphism (SNP), 135G>C in the 5'UTR of the RAD51 gene, affects gene transcription activity with implications for the repair of damaged DNA related to tumorigenesis. Previous limited reported genetic studies to link the 135G>C polymorphism of RAD51 gene to the risk of gastrointestinal tract (GIT) cancers, especially esophageal cancer (EC), have been inconclusive.
Materials and Methods: The polymorphism was evaluated by RFLP-PCR in 252 EC patients and 252 healthy controls from Amritsar, Punjab, India, for case–control study. For a meta-analysis, a total of 78 studies on GIT cancers were assessed, out of which 14 eligible studies (including the present study) comprising 2842 cases and 3224 controls were included. Odds ratios (ORs) with 95% confidence intervals (CIs) and Chi-square test were used to assess the association in different inheritance models.
Results: The GC genotype (OR: 0.45, 95% CI: 0.29–0.68) and C allele (OR: 0.52, 95% CI: 0.36–0.75) were significantly lower (P = 0.0005) in cases as compared to controls. There was no significant association with any genetic model in the meta-analysis.
Conclusion: C allele provides protection for EC in the studied population contrary to previous reports in Polish, Chinese population probably due to ethic differences. Compared with previous meta-analysis on individual GIT cancers, present meta-analysis included all GIT cancers but found no association.

Keywords: Esophageal cancer, gastrointestinal tract cancer, meta-analysis, polymorphism, RAD51



How to cite this URL:
Bali JS, Sambyal V, Guleria K, Mehrotra S, Singh NR, Uppal MS, Manjari M, Sudan M. RAD51 135G>C polymorphism in esophageal cancer and meta-analysis in gastrointestinal tract cancers. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=329059




 > Introduction Top


Esophageal cancer (EC) is the seventh most common cancer in the world. A vast majority of EC cases occur in developing countries. The incidence and mortality rates in different regions of the world have more than 2- to 3-fold differences in both sexes, with lower rates in Polynesia and Western Africa and higher rates in Eastern Asia.[1] Among the histological types of EC, squamous cell carcinoma (SCC) is predominant worldwide. In Australia, Finland, France, United Kingdom, and United States, adenocarcinoma (AC) of esophagus is prevalent.[2] Sarcomas or small cell carcinomas of esophagus have a low prevalence of <1%–2%.[3] SCC develops mostly in the upper 2/3rd of the esophagus, whereas AC usually develops in the lower one-third of the esophagus.[4] In India, 52,396 cases of EC were newly diagnosed and 46,504 deaths were reported in 2018 as compared to 572,000 new cases and 509,000 deaths worldwide.[1] In India, the states of Assam, Meghalaya, Mizoram, and Nagaland are the leading sites for EC followed by Kashmir valley. SCC is the most common type in India.[5] EC is the sixth leading cause of cancer patient deaths in the world and the fourth leading cause in India. In spite of various advances in diagnosis and treatment of EC, the 5-year survival rate among patients ranges from 4% to 40% depending on stage, with an overall 5-year survival rate of 18%.[6]

Development of cancer is characterized by unstable genome and clonal evolution of malignant cells. To maintain genomic stability in cells, various DNA repair pathways counter DNA damage. Homologous recombination repair (HRR) is one such repair pathway, which plays a key role in somatic mammalian cells during and following DNA replication. The central protein in HRR in eukaryotes is RAD51, coded by RAD51 gene (chromosomal locus 15q15.1). It repairs DNA double-strand breaks by catalyzing strand transfer.[7],[8] RAD51 protein is responsible for formation of nucleoprotein filaments on single-stranded DNA, which in turn induces homologous pairing and carries out strand exchange reactions between single- and double-stranded DNA.[9],[10] Minor changes in RAD51 have been reported to lead to DNA instability, resulting in increased malignancies. Single-nucleotide polymorphisms (SNPs) (135G>C and 172G>T) have been discovered in 5' untranslated region (UTR) of RAD51 till now. However, the former one has been the focus of many published studies due to its key role in maintenance of genomic stability. The SNP at position 135 in 5' UTR of RAD51 (rs1801320) has been found to regulate the expression of RAD51 protein by affecting mRNA stability or translational efficiency, resulting in RAD51 protein dysfunction, thus infi‚uencing the DNA repair capacity.[11],[12],[13]

Multiple molecular epidemiological studies have assessed the association between cancer risk and RAD51 135G>C polymorphism, but the results remain inconclusive. Some studies[14],[15],[16],[17] showed that this polymorphism is significantly associated with increased cancer risk, whereas one study found reduced risk[18] and few failed to find any association.[19],[20],[21],[22] Several reports indicating the involvement of RAD51 135G>C polymorphism in the development of tumor through HRR led us to study this polymorphism in our population.

Punjab, an agrarian state of India located in North-West between 29”30'N-32”32'N and 73”55'E-76”50'E longitude, is reporting increasing incidence of cancer with EC being common in both males and females.[5] From Punjab, India, no previous study was reported on this polymorphism in EC. Therefore, a case–control study was performed on 504 subjects comprising 252clinically confirmed cases of EC and 252 controls from Amritsar, Punjab, to evaluate statistical evidence of the association if any between RAD51 135G>C polymorphism and EC risk. A meticulous meta-analysis was then performed by including the relevant and most recent articles for gastrointestinal tract (GIT) cancers including EC.


 > Materials and Methods Top


Case–control study

Subject selection and collection of genetic material

In this case–control study, peripheral blood samples of EC patients were collected after informed consent. The ethical clearance for the current study was obtained from the institutional ethics committee under tenets of the Declaration of Helsinki. Cases having HIV, hepatitis, and other cancers or patients having received chemotherapy or radiotherapy were not included in the study. Information of their age, sex, habits such as smoking and alcohol consumption, occupational status, dietary habits, and habitat were recorded.

Screening of RAD51 135G > C polymorphism

Extraction of genomic DNA from whole blood was performed using standard phenol chloroform method.[23] The PCR amplification was performed using the following primers: Forward Primer: 5'-TGGGAACTGCAACTCATCTGG-3' and Reverse Primer: 5'-GCTCCGACTTCACCCCGCGG-3'.[21] Conditions for PCR were initial denaturation at 95°C for 5 min and then 34 cycles of 95°C for 30 s, 64°C for 45 s, 72°C for 30 s, and final elongation step 72°C for 10 min The resulting amplified PCR products consist of 131 bp region around the nucleotide 135. The PCR product of 131 bp was digested with BstN1 restriction enzyme according to the instructions given by the manufacturer New England Biolabs (NEB). In homozygous wild type (GG), the amplified product was digested into two fragments of 71 bp and 60 bp. In heterozygous condition, three fragments of 131 bp, 71 bp, and 60 bp were obtained. In homozygous mutant type (CC), single fragment of 131 bp was obtained.

Logistic regression analysis was performed to compare the genotypic frequency distribution between EC cases and controls. The test of significance was calculated using odds ratios (ORs) and their 95% confidence intervals (95% CIs) and adjusted for the effect of age. P < 0.05 was considered statistically significant.

Meta-analysis

Strategy of search

All reported studies involving the association between risk of several GIT cancers and RAD51 135G>C polymorphism were identified by comprehensive computer-based literature searches of Embase, Google scholar, PubMed, and Web of Science (up to April 31, 2020). For search, the following keywords were used: “RAD51” or “RAD51 gene” AND (”polymorphism” or “genetic variant” or genetic variations”) AND (”esophageal cancer or oral cancer or pharynx cancer or larynx or nasopharynx cancer or colorectal cancer or liver cancer or gastric cancer”). In addition, studies were also identified by searching manually the reference lists of reviews and retrieved studies.

Criteria for inclusion and exclusion

The studies meeting the following criteria were included in the meta-analysis: (a) had case–control designs, (b) evaluated the effect of RAD51 135G>C polymorphism with GIT cancer risk, (c) genotype frequencies of healthy controls were in accordance with the Hardy–Weinberg equilibrium (HWE), (d) sufficient data (genotype distributions for cases and controls) were available to calculate an OR with its 95% CI, and (e) studies were published in English. Exclusion criteria were as follows: (a) not case–control studies, (b) the genotype distribution among controls were not in HWE, and (c) studies contained duplicate data.

Data extraction

Extraction of data from the eligible publications was done according to the inclusion and exclusion criteria. An agreement was reached following a discussion, for conflicting evaluations. Study characteristics extracted from each article were as follows: name of the first author, year of publication, country of origin, ethnicity, type of cancer, source of control, method of genotyping, number of cases and controls, genotype frequency and allele frequency in cases and controls, and evidence of HWE in controls. The ethnic classification was done as “Asian,” “Caucasians,” and “mixed.”

Statistical analysis

In the controls, for each study, HWE was analyzed using goodness-of-fit test (Chi-square). The violation of HWE was determined by P < 0.05. ORs with 95% CI were calculated to determine the strength of the association between the cancer risk and RAD51 gene polymorphism. The pooled ORs with corresponding 95% CI for RAD51 135G>C polymorphism were determined under dominant model (GC + CC vs. GG), recessive model (CC vs. GC + GG), homozygote model (CC vs. GG), codominant model (CC vs. GC and GC vs. GG), and allele model (C vs. G). To test the heterogeneity across the eligible comparisons, a Chi-square-based Q-test was performed, which was considered to be significant if P < 0.05. In addition, the percentage of total variation due to heterogeneity was quantified by the I2 value. If P ≥ 0.05 and I2 < 50%, we used the fixed effects model (the Mantel–Haenszel method) for pooling the results. Otherwise, the random effects model (the DerSimonian–Laird method) was used. Begg's funnel plot and sensitivity analysis was used to address the potential publication bias. RStudio (version 1.1.463 RStudio, PBC, Boston, MA) was used to perform all the statistical tests.


 > Results Top


Case–control study

Characteristics of the study population

In the present study, 252 sporadic EC patients (148 females and 104 males) and 252 unrelated healthy controls (148 females and 104 males) were screened. The mean age of patients was 55.75 ± 12.79 and of controls was 55.87 ± 12.40 years. Out of 252 EC patients, 197 patients were from rural areas and 55 patients were from urban areas.

Data analysis

In EC patients and controls, the distribution of genotypes and allele frequencies of RAD51 135G>C polymorphism is presented in [Table 1]. All genotypes in the control group were in Hardy–Weinberg equilibrium (P > 0.05). A statistically significant association of RAD51 135G>C polymorphism with EC risk was observed, as frequency of GC genotype was much lower in EC patients as compared to controls. Similar difference was observed in case of allele frequencies, as the frequency of C allele was lower in EC patients than controls. Association analysis revealed that GC genotype (OR = 0.45, CI: 0.29–0.68, P = 0.0002) and C allele (OR = 0.52, CI: 0.36–0.75, P = 0.0005) conferred protection from EC risk.
Table 1: Distribution of genotypes and allele frequencies of RAD51 135G>C polymorphism in esophageal cancer patients and controls

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Studies included in the meta-analysis

A total of 78 records of publications were yielded after preliminary search. On the basis of the predefined criteria for inclusion and exclusion, 14 case–control studies from 12 publications including our present study were included in this meta-analysis [Figure 1]. A recent study by Hridy et al. 2020[24] was excluded as the reference allele considered by the authors differed from our study. These 14 studies included a total of 6,066 subjects (2842 cases and 3224 controls). As the study of Santos et al. in 2018 included two different groups of cases (oral and oropharyngeal), this study was considered as two different studies each. The HWE test showed that the genotype distribution of the controls was in agreement with HWE. Of these 14 studies, 7 were on Caucasians, 5 were on Asians, and 2 were on mixed population. The characteristics of these studies are depicted in [Table 2].
Figure 1: The flow diagram of the literature search and the study selection for meta-analysis

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Table 2: Summary of studies included in the meta-analysis

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Pooled analysis

The meta-analysis results are shown in [Table 3]. There was no significant heterogeneity across all levels of analysis, thus justifying the choice of the fixed effects model for analysis. Further, we have conducted analyses using all genetic models to efficiently characterize the association between RAD51 135G>C substitution and GI tract cancer risk. Overall, no significant association was found between RAD51 135G>C polymorphism and GI tract cancer risk in any genetic model (dominant model: GC + CC vs. GG, OR = 0.96, P = 0.69 [Figure 2]; recessive model: CC vs. GG + GC, OR = 1.23, P = 0.31; homozygote model: CC vs. GG, OR = 1.25, P = 0.27 [Figure 3]; codominant model: CC vs. GC, OR = 1.23, 95% CI = 0.82-1.86 P = 0.31; GC vs. GG, OR = 0.95, 95%CI = 0.76-1.18 P = 0.63; and allele model: C vs. G, OR = 0.96, 95%CI = 0.80-1.15 P = 0.66).
Figure 2: Forest plot showing association of gastrointestinal tract cancer risk and RAD51 135G>C polymorphism (dominant model, GC + CC vs. GG)

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Figure 3: Forest plot showing association of gastrointestinal tract cancer risk and RAD51 135G>C polymorphism (homozygote model, CC vs. GG)

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Table 3: Meta-analysis results using different genetic models

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On the basis of ethnicity also in pooled analysis, no significant association was found between RAD51 135G>C substitution and GI tract cancer risk in Caucasian (dominant model: OR = 1.03, P = 0.76; recessive model: OR = 1.34, P = 0.37; homozygote model: OR = 1.41 P = 0.29; codominant model: CC vs. GC, OR = 1.25, P = 0.50; GC vs. GG, OR = 1.01, P = 0.92; and allele model: OR = 1.05, P = 0.60) as well as in Asian ethnicity (dominant model: OR = 0.88, P = 0.55; recessive model: OR = 1.26, P = 0.39; homozygote model: OR = 1.26, P = 0.39; codominant model: GC vs. GG, OR = 0.87, P = 0.51; CC vs. GC, OR = 1.33, P = 0.31; and allele model: OR = 0.90, P = 0.57) [Table 4].
Table 4: Meta-analysis results on the basis of ethnicity

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Sensitivity analysis

To determine the stability of the results in our meta-analysis, we performed sensitivity analysis. Statistically similar results were obtained after removing each study sequentially, indicating statistically reliable results of our meta-analysis.

Publication bias

Begg's funnel plot and egger's test were used to assess the publication bias for the included studies. No publication bias was observed in Begg's funnel plots as shape of the plots showed to be symmetrical [Figure 4] and [Figure 5], and in egger's test also, no publication bias was observed (P = 0.64 for GC + CC vs. GG and P = 0.24 for CC vs. GG).
Figure 4: Begg's funnel plot for publication in bias in the selection of studies on RAD51 135G>C polymorphism (dominant model, GC + CC vs. GG)

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Figure 5: Begg's funnel plot for publication bias in the selection of studies on RAD51 135G>C polymorphism (homozygote model, CC vs. GG)

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 > Discussion Top


Cell division period is critical in terms of exposure to adverse rearrangements in the genome which are induced by DNA double-strand breaks.[25] HRR and nonhomologous end joining are two major pathways for double-strand repair, which is an important DNA repair mechanism.[26] Repair of damage by homologous recombination (HR) is a crucial pathway in somatic mammalian cells[13] and RAD51 is one of its central proteins. It is encoded by RAD51 gene and plays a key role in HR by participating in strand invasion, polymerization, and annealing of the resulting nucleoprotein filament to a complementary homologous strand on the intact DNA.[12],[27],[28],[29]

Increased levels of RAD51 and number of cells with nuclear RAD51 foci have been demonstrated in a wide variety of tumor cells. The constitutive overexpression of RAD51 in tumor cells can be expected to create imbalance between different components of DNA repair system. The enhanced levels of RAD51 protein may protect the tumor cells from undergoing apoptosis in response to DNA damage.[30] The elevated protein levels can be caused by transcriptionally upregulated RAD51 gene. The G/C substitution at position 135 is found in 5' UTR, so it is speculated to exert an influence on RAD51 protein's overexpression, thus increasing the regulation of DNA repair during transcription.[9],[31]

We have performed a case–control study involving 252 cases and 252 controls to evaluate the association between RAD51 135G>C polymorphism and EC risk. The overall analysis showed a significant risk reduction of EC in RAD51 135G>C GC genotype carriers. The results were contradictory to the results reported from two Chinese studies, where in one study, C allele carriers were at a higher risk of developing EC,[32] whereas no association was observed in the other study.[22] To investigate the reason behind this contradiction, a thorough review of literature was performed, but a very limited data were available on association between RAD51 135G>C polymorphism and EC risk. Therefore, a meta-analysis was performed to assess the association between RAD51 135G>C polymorphism and risk of other GIT cancers in addition to EC.

The meta-analysis included 2842 cases and 3224 controls from 14 case–control studies. The overall analysis did not show any significant association between RAD51 135G>C polymorphism and risk of various GIT cancers in any genetic model. Whereas, significant associations were reported in previously published meta-analysis on individual cancers of GIT, significant association with increased risk of SCCHN,[33] significant association with HNC risk under allele comparison,[34] and significant association with increased risk of CRC.[35],[36] Similarly, a comprehensive meta-analysis found significant association with increased risk of CRC under homozygote, recessive, and allele models.[10] Compared with all previous studies, ours is the first meta-analysis, which included all GIT cancers, but no significant association was seen in meta-analysis. This difference is probably due to differences in ethnic background of population studied. Most of the studies included in the meta-analysis are from Chinese (Mongoloid) and Polish (Caucasian) population, whereas our population group has mixture of Caucasian–Scythians racial elements.[37],[38]

However, the present meta-analysis has some limitations: (a) most of the studies included in the meta-analysis are from Asian and Caucasian descent only and many studies have relatively very small sample size, so statistical power is not enough to explore the real association; (b) significant heterogeneity was observed among the included studies; (c) cancer is a multifactorial disease and our meta-analysis is based on some limited factors; and (d) only those articles are included in our meta-analysis which are published in English language whereas articles in other languages (n = 2) are not included.

The present case–control study is the first report from Punjab, which reports the association of RAD51 135G>C polymorphism with EC risk, thus providing baseline data from Punjab, North-West India. Majority of the patients (78%) in the present study belonged to rural area and were directly or indirectly exposed to agrochemicals owing to their involvement in agricultural activities.[39] Hence, screening of this population for DNA repair genes like RAD51 can help assess the risk of EC in exposed individuals, which can further influence the choice of treatment modalities.


 > conclusion Top


No significant association was found in meta-analysis, whereas protective role of GC genotype was observed for RAD51 135G>C polymorphism in our case–control study.

Financial support and sponsorship

Financial assistance from University Grant Commission, India vide UGC-UPE and UGC-CPEPA to Dr. Vasudha Sambyal and Dr. Kamlesh Guleria and Research fellowship from UGC-UPE to Jagmohan Singh Bali is highly acknowledged.

Conflicts of interest

There are no conflicts of interest.







 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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