Arg399Gln Polymorphism Research Articles

The XRCC1 Arg194Trp polymorphism is significantly associated with lung adenocarcinoma: a case-control study in an Eastern European Caucasian group.

DNA repair plays an important role in maintaining the integrity of the genome by repairing DNA damage induced by carcinogens. Certain genetic polymorphisms that occur in DNA-repair genes may affect the ability to repair DNA defects, and may represent a risk factor in carcinogenesis. The gene XRCC1 is involved in DNA repair. The purpose of our study was to investigate the association between XRCC1 Arg194Trp and Arg399Gln polymorphisms and the risk of lung cancer in a Romanian population. We recruited 222 healthy controls and 102 patients with lung cancer. Genotypes were determined by multiplex polymerase chain-reaction restriction fragment-length polymorphism. Statistical analysis (odds ratio, recessive model) revealed an increased risk for lung cancer for the homozygous 194Trp genotype (χ2=0.186, odds ratio 10.667, 95% confidence interval 1.309–86.933; P=0.007). Also, we found an association between the 194Trp allele and women with lung adenocarcinoma. In conclusion, the results of the study place the XRCC1 Arg194Trp polymorphism among independent risk factors for developing lung cancer.

The association between XRCC1 Arg399Gln polymorphism and risk of leukemia in different populations: a meta-analysis of case-control studies.

BackgroundAssociations between Arg399Gln single-nucleotide polymorphism (SNP) in the XRCC1 gene and leukemia susceptibility have been studied extensively, however, the results are inconsistent. The aim of this study was to determine these associations using meta-analytical methods.MethodsA meta-analysis was performed to examine the associations between XRCC1 Arg399-Gln SNP and leukemia risk. A literature search of PubMed and Web of Science databases was conducted to identify relevant studies published up to March 10, 2015. The references of the retrieved articles were also screened. All the statistical analyses were conducted using Review Manager software.ResultsThe XRCC1 Arg399Gln SNP was found to be associated with increased childhood risk of acute lymphoblastic leukemia among Asians under the dominant (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.50–2.97, P<0.0001), allele contrast (OR 1.72, 95% CI 1.33–2.23, P<0.0001), and homozygote contrast (OR 2.34, 95% CI 1.25–4.36, P=0.008) models. However, no association was found in Caucasians between the SNP and risk of either chronic myeloid leukemia or chronic lymphocytic leukemia under any contrast model.ConclusionThe findings of the current meta-analysis indicate that the XRCC1 Arg399Gln SNP is a risk factor for childhood lymphoblastic leukemia in Asians.

Base Excision Repair Gene XRCC1 (Arg280His) and (Arg399Gln) Polymorphisms Are Associated With Oesophageal Cancer Risk but (Arg194Trp) Is Not in Northeast Indian Population

Base Excision Repair Gene XRCC1 (Arg280His) and (Arg399Gln) Polymorphisms Are Associated With Oesophageal Cancer Risk but (Arg194Trp) Is Not in Northeast Indian Population

Impact of RAD51 G135C and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women.

The polymorphic variations of DNA repair genes may contribute to functional deficiencies in DNA repair processes increasing susceptibility to cancer. We aimed to investigate the impact of 135G>C RAD51 and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women. The study included 50 ovarian carcinoma samples and 78 cervical swabs of gynecologically healthy age-matched controls. RAD51 G135C and XRCC1 Arg399Gln polymorphisms were determined by PCR-RFLP. Deviations of the genotype frequencies from Hardy-Weinberg equilibrium were assessed using the χ2 test. The allele- and genotype-specific risks were estimated as odds ratios with 95% confidence intervals. RAD51 135C and XRCC1 Arg allele are associated with ovarian carcinoma [OR (95% CI): 2.54 (1.22-5.29) for C vs. G; 2.64 (1.53-4.55) for Arg vs. Gln]. RAD51 C exerts its effect in dominant (CC plus GC vs. GG) [OR (95% CI): 2.83 (1.21-6.62], while XRCC1Arg in dominant (ArgArg plus ArgGln vs. GlnGln) [OR (95% CI): 4.76 (1.69-13.42)] and recessive model (ArgArg vs. ArgGln plus GlnGln) [OR (95% CI): 2.21 (1.07-4.56)]. The results suggest that the RAD51 G135C and XRCC1 Arg399Gln polymorphisms could be biomarkers of susceptibility for ovarian carcinoma development. Further larger case-control study is needed to confirm our findings.

Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene: Haplotypes, Breast Cancer Risk and Individual Radiosensitivity

The aim of this paper is to analyse the role exerted by X-ray repair cross-complementing group 1 (XRCC1) genetic polymorphisms and haplotypes in increasing breast cancer risk and in modulating radiotherapy-induced adverse reactions. An Italian cohort of breast cancer patients and a matching group of healthy controls were genotyped for XRCC1-77T&gt;C, Arg194Trp and Arg399Gln polymorphisms. Our data indicated that polymorphisms at codon 399 and at -77 position of the 5’-untraslated region both contribute to cancer risk. We also showed that the haplotype H3, containing the wild-type allele at codon 194 and the variant alleles at codon 399 and at -77 position is significantly associated with an increased risk of breast cancer. We found no statistical association between XRCC1 SNPs and individual radiosensitivity.

DNA Repair Gene Polymorphisms and Their Relation With DNA Damage, DNA Repair, and Total Antioxidant Capacity in Childhood Acute Lymphoblastic Leukemia Survivors

Oxidative stress and defective DNA repair are major contributory factors in the initiation and progression of carcinogenesis. Chemotherapy and radiotherapy cause oxidative DNA damage, consume antioxidant capacity, and impair DNA repair activity. These effects of chemotherapy and radiotherapy may be contributory factors in the development of secondary malignancy in cancer survivors. Basal, H2O2-induced, and postrepair DNA damage; urinary 8-hydroxydeoxyguanosine level as a marker of oxidatively damaged DNA; and serum total antioxidant capacity were measured; XPD Lys751Gln, XRCC1 Arg399Gln, and XRCC1 Arg194Trp polymorphisms were analyzed in childhood acute lymphoblastic leukemia (ALL) survivors. Basal and H2O2-induced DNA damage were found to be higher in the ALL survivor group versus the control group, however, there was no significant difference between the other parameters. No association was found between the examined parameters and polymorphisms of XPD 751 and XRCC1 399 and both the groups. XRCC1 194Trp allele was found to be associated with a low level of postrepair DNA damage in the ALL survivors. In conclusion, basal DNA damage and susceptibility to oxidation are high in childhood ALL survivors. This situation which may easily lead to occurrence of a secondary cancer does not seem to be a result of deficient DNA repair.

Association of XRCC1 Arg399Gln Polymorphism with Colorectal Cancer Risk: A HuGE Meta Analysis of 35 Studies

Non-synonymous polymorphisms in XRCC1 hase been shown to reduce effectiveness of DNA repair and be associated with risk of certain cancers. In this study we aimed to clarify any association between XRCC1 Arg399Gln and colorectal cancer (CRC) risk by performing a meta-analysis of published case-control studies. PubMed and Google Scholar were searched to explore the association between XRCC1 and CRC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias was assessed by Egger's and Begg's tests. Up to January 2015, 35 case control studies involving 9,114 CRC cases and 13,948 controls were included in the present meta-analysis. The results showed that the Arg399Gln polymorphism only under an allele genetic model was associated with CRC risk (A vs. G: OR 0.128, 95% CI 0.119-0.138, p<0.001). Also, this meta-analysis suggested that the XRCC1 Arg399Gln polymorphism might associated with susceptibility to CRC in Asians (A vs G: OR 0.124, 95% CI 0.112-0.138, p<0.001) and Caucasian (A vs G: OR 0.132, 95% CI 0.119-0.146, p<0.001) only under an allele genetic model. This meta-analysis confirms the association between XRCC1 Arg399Gln polymorphism and CRC risk and suggests that the heterogeneity is not strongly modified by ethnicity and deviation from the Hardy-Weinberg equilibrium.

Updated assessment of the association of the XRCC1 Arg399Gln polymorphism with lung cancer risk in the Chinese population.

Published studies have reported relationships between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and lung cancer risk in Chinese population. However, the epidemiological results remained controversial. The objective of this study was to clarify the association of XRCC1 Arg399Gln polymorphism with lung cancer risk in the Chinese population. Systematic searches were performed through the database of Medline/Pubmed, Web of Science, Embase, CNKI and WanFang Medical Online. Odds ratios (ORs) with 95% confidence interval (95%CI) were calculated to estimate the strength of the association. Overall, we observed an increased lung cancer risk among subjects carrying XRCC1 codon 399 Gln/Gln genotype (OR=1.36, 95%CI: 1.09-1.71) in the Chinese population on the basis of 19 studies with 5,416 cases and 5,782 controls. We did not observe any association between XRCC1 codon 399 Arg/Gln and Arg/Gln+Gln/Gln polymorphisms and lung cancer risk (OR=1.00, 95%CI: 0.92-1.08 and OR=1.05, 95%CI: 0.97- 1.13, respectively). Limiting the analysis to studies with controls in agreement with Hardy-Weinberg equilibrium (HWE), we observed an increased lung cancer risk among subjects carrying XRCC1 codon 399 Gln/Gln genotype (OR=1.18, 95%CI: 1.01-1.38). When stratified by source of control, we observed an increased lung cancer risk among subjects carrying XRCC1 codon 399 Arg/Gln+Gln/Gln genotype on the basis of hospitalized patient-based controls (OR=1.21, 95%CI: 1.04-1.42) and among subjects carrying XRCC1 codon 399 Gln/Gln genotype on the basis of healthy subject-based controls (OR=1.22, 95%CI: 1.04-1.43). Our findings indicated that certain XRCC1 Arg399Gln variants might affect the susceptibility of lung cancer in Chinese population. Larger sample size studies are required to confirm our findings.

Polymorphisms of the XRCC1 gene and breast cancer risk in the Mexican population.

The purpose of this case-control study was to evaluate the association of XRCC1 Arg194Trp and Arg399Gln polymorphisms with susceptibility to breast cancer (BC) in a Mexican population. We analysed DNA samples from 345 BC patients and 352 control subjects by polymerase chain reaction-restriction fragment length polymorphism. The frequency of the 399Gln allele was 23% in controls and 29% in patients [OR 1.38 (1.08-1.76); p = 0.01]; genotypes in controls were 60, 36, and 4% for Arg/Arg, Arg/Gln, and Gln/Gln, respectively, while in patients they were 53, 36, and 11% [OR 2.71 (1.44-5.10); p = 0.0015 for the Gln/Gln genotype]. Regarding the Arg194Trp polymorphism, the frequency of Trp allele was 15% in controls and 16% in patients [OR 1.09 (0.82-1.46); p = 0.54]; the genotype frequencies in controls were 74, 23, and 3% for Arg/Arg, Arg/Trp and Trp/Trp, respectively, while in patients these were 73, 23, and 4% [OR 1.41 (0.64-3.14); p = 0.39 for the Trp/Trp genotype]. Allele frequencies were consistent with Hardy-Weinberg equilibrium (p = 0.20 for Arg194Trp and p = 0.54 for Arg399Gln). Our results indicate that the 399Gln polymorphism is associated with an increased risk of BC. Additionally, we found that some covariates increase the risk of BC in Mexican women; namely, antecedent of abortions [OR 3.69 (2.17-6.27); p < 0.001], not breastfeeding [OR 2.46 (1.45-4.18); p = 0.001], family history of BC [OR 15.9 (5.09-50.23); p < 0.001], other type of family cancer [OR 31.5 (12.5-79.3); p < 0.001], alcoholism [OR 17.7 (5.2-60.42); p < 0.001], type 2 diabetes mellitus [OR 2.28 (1.26-4.10); p = 0.007], and contraceptive use [OR 2.28 (1.26-4.10); p < 0.001].

The Arg399Gln polymorphism in the XRCC1 gene is associated with increased risk of hematological malignancies.

The associations between the Arg399Gln polymorphism in X-ray repair cross-complementing gene 1 (XRCC1) gene and the risk of hematological malignancies have been extensively investigated. However, the results were inconsistent. The objective of the current study is to investigate the association by meta-analysis. We searched PubMed database, Embase database, CNKI database, Wanfang database, and Weipu database, covering all studies until August 7, 2013. Statistical analysis was performed by using the Revman4.2 software and the Stata10.0 software. A total of 27 case-control studies concerning the Arg399Gln polymorphism were included from 26 articles. The results suggested that the Arg399Gln polymorphism was not associated with an increased/decreased risk of hematological malignancies in total analysis (OR = 1.15, 95 % confidence interval (CI) = 0.97-1.35, P = 0.10 for Arg/Gln + Gln/Gln vs. Arg/Arg). In the subgroup analysis by ethnicity and cancer types, significant association was found in Asians (OR = 1.35, 95 % CI = 1.04-1.75, P = 0.03) but not in Europeans (OR = 1.07, 95 % CI = 0.86-1.33, P = 0.56), and in leukemia (OR = 1.25, 95 % CI = 1.02-1.54, P = 0.03) but not in lymphoma (OR = 0.98, 95 % CI = 0.80-1.20, P = 0.84) or myeloma (OR = 1.13, 95 % CI = 0.23-5.69, P = 0.88). The current meta-analysis indicated that the Arg399Gln polymorphism in the XRCC1 gene might be a risk factor for hematological malignancies in Asians or for leukemia. In future, more large-scale case-control studies are needed to validate these results.

Prognostic value of ERCC1, ERCC2, XRCC1, and TP53 single nucleotide polymorphisms in patients with early-stage non-small cell lung cancer.

Identification of biomarkers used for the prognostic evaluation of non-small cell lung cancer (NSCLC) patients is important. The aim of this study was to evaluate the potential prognostic value of XRCC1, ERCC1, ERCC2, and TP53 single nucleotide polymorphisms (SNPs) in completely resected NSCLC patients. In total, 130 patients, surgically treated for NSCLC between 2000 and 2012, were included. An analysis of SNPs from peripheral blood cells was performed by polymerase chain reaction. XRCC1 Arg399Gln, ERCC1 Asn118Asn, ERCC2 Lys751Gln, and TP53 Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters and survival. Kaplan-Meier method and Cox regression analysis were used. Median age rate was 59.3, ranging between 36 and 78 years. Median relapse-free survival duration (RFS) was found as 46.2 months. In those with ERCC2 CC allele, median RFS was detected as 28.3 months (95 % confidence interval (CI), 20.8-35.8), 46.9 months in those with CT heterozygous (95 % CI, 18.6-75.2), and 80.1 months for those with TT mutant allel (95 % CI, 33.0-127.2). Median RFS was seen to be longer in mutant group and also statistically significant (P = 0.018). Additionally, upon evaluating CC normal group with CT + TT alleles including mutant alleles, median RFS was found as 56.5 months (95 % CI, 24.6-88.4) in CT + TT group, and this was statistically significant (P = 0.005) Also, median RFS was 15.1 months in those including ERCC2 CC allele and 56.5 months in CT + TT allele in the group with no adjuvant treatment (P = 0.001). In conclusion, our study showed that ERCC2/XPD polymorphism is an independent prognostic factor in operated NSCLC patients, and these findings should be supported with prospective studies.

Association between the XRCC1 Arg399Gln polymorphism and risk of cervical carcinoma: a meta-analysis.

Numerous studies have evaluated the association between Arg399Gln polymorphism of DNA repair gene XRCC1 and cervical carcinoma risk. However, the specific association is still controversial. To assess the relationship between XRCC1 Arg399Gln polymorphism and cervical carcinoma, we conducted a comprehensive meta-analysis of 10 case-control studies with 2051 cervical carcinoma cases and 2919 controls. Meta-analysis results based on all the studies showed a significant association between XRCC1 Arg399Gln polymorphism and cervical carcinoma risk (GlnGln vs ArgArg: OR = 1.29, 95%CI = 0.90-1.85; GlnGln vs ArgGln: OR = 1.15, 95%CI = 0.93-1.43; the dominant model: OR = 0.80, 95%CI = 0.66-0.99; the recessive model: OR = 1.18, 95%CI = 0.93-1.49). In the subgroup analysis by ethnicity, the results also showed significant association between XRCC1 Arg399Gln polymorphism and susceptibility to cervical carcinoma in both Caucasian and Asian populations. The Arg399Gln polymorphism in the XRCC1 gene may be related to the increased risk of cervical carcinoma. Conclusive evidence on the effects of the variants in cervical carcinoma should be addressed in further studies.

Research of DNA repair genes polymorphism XRCC1 and XPD and the risks of thyroid cancer development in persons exposed to ionizing radiation after Chornobyl disaster

The objective of this work was to determine and compare the features of DNA repair gene XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in patients with thyroid cancer (TC), who were exposed to ionizing radiation (IR) as a result of the Chornobyl disaster, and in patients without exposure to ionizing radiation in history. Determination of gene XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms was performed by polymerase chain reaction (PCR) in 102 patients with thyroid cancer: 38 people, who were exposed to ionizing radiation due to Chornobyl disaster (members of the accident, and evacuees and residents from controlled areas contaminated with radionuclides), 64 individuals without exposure to ionizing radiation in history and 41 persons residents of Ukraine without cancer pathology in the control group. For comparison of the data on spontaneous and radiation-associated thyroid cancer and settlement of allele frequencies differences and risk of cancer pathology were used the literature data on control groups of populations of Russia, Belarus and Poland. Comparing to the literature data on XRCC1 Arg399Gln polymorphisms in radiation-exposed individuals without cancer pathology, the risk of thyroid cancer in homozygous minor allele XRCC1 Gln399Gln carriers, who were exposed to ionizing radiation was significantly increased: OR = 4,14, p = 0,001 (CI95 % 1,72-9,93). In homozygous carriers of the minor allele of the gene XPD Lys751Gln, exposed to IR, revealed increased risk of thyroid cancer: OR = 3,30, p = 0,05 (CI 95 % 0,82-14,14), when compared with the control group of Ukrainian population. The carriage of homozygous minor allele Gln399Gln XRCC1 and XPD Gln751Gln of DNA repair genes is a risk factor for thyroid cancer under the influence of ionizing radiation in research group of Ukrainian population.

X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism significantly associated with prostate cancer.

Prostate cancer (Pca) is one of the noncutaneous cancers occurring worldwide. Its high morbidity and mortality make it a concern. X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism (rs25487) has been reported to be related to Pca. However, the conclusions are controversial. In this study, PubMed, HuGENet and Chinese National Knowledge Infrastructure (CNKI) databases were combined with a comprehensive literature search. Four models including dominant (AA + AG vs. GG), recessive (AA vs. AG+GG), codominant (AA vs. AG, AA vs. GG) and per-allele analysis (A vs. G) were applied. Finally, 15 studies with 18 sets of data were included. A positive association was discovered in pooled results for recessive (odds ratio [OR]=1.202, 95% confidence interval [95% CI], 1.060-1.363, I2=46.20%), codominant (AA vs. AG; OR=1.258, 95% CI, 1.099-1.439, I2=38.50%; AA vs. GG; OR=1.283, 95% CI, 1.027-1.602, I2=51.70%) and allele analysis (OR=1.116, 95% CI, 1.001-1.244, I2=58.00%). In ethnicity subgroup analysis, these 4 models were also significant in the Asian subgroup. However, for whites, only 2 models seemed to be significant (AA vs. AG+GG: OR=1.525, 95% CI, 1.111-2.093, I2=52.60%; AA vs. AG: OR=1.678, 95% CI, 1.185-2.375, I2=30.70%). In further analysis, we regrouped the data based on race, in which pooled results and Asian subgroup were again shown to be positive. In the next analysis, expression quantitative trait loci (eQTL), linkage disequilibrium (LD), TagSNP and functional analysis were used. The results showed that the SNP was a tag and functional SNP with LD block in both Asians and whites. In summary, we suggest that XRCC1 Arg399Gln might be significantly associated with development of Pca.

Association of XRCC1 Arg399GIn and Tp53 Arg72Pro polymorphisms and increased risk of uterine leiomyoma - A case-control study.

The aim of present study was to investigate the role of the X-ray repair cross-complementing protein1 (XRCC1) and Tumor protein p53 (Tp53) polymorphisms in Uterine Leiomyoma (UL) susceptibility in southeastern Iran. This case control study was performed on 139 women with UL and 149 age, BMI and ethnicity matched healthy women. All women were genotyped for the XRCC1 Arg399Gln, XRCC1 Arg194Trp and Tp53 Arg72Pro polymorphisms. The frequency of Tp53 72 Pro/Pro genotype was significantly higher in UL women compared to controls. The risk of UL was 1.5 fold higher in women with the Pro/Pro genotype (OR, 1.5 [95% CI, 1.1 to 2.1], p = 0.012). Moreover, the frequency of the Pro allele was significantly higher in the UL women. Although the frequency of XRCC1 Arg399Gln genotypes did not significantly differ between UL and control groups before adjusting for age, there was an association between the XRCC1 Arg/Gln genotype and UL after adjusting for age (OR, 1.8 [95% CI, 1.1 to 3]). No association was observed between the XRCC1 Arg194Trp polymorphism and UL. The Pro/Pro genotype of Tp53 Arg72Pro polymorphism was associated with UL susceptibility. In addition, the XRCC1 Arg/Gln genotype was associated with increased risk of UL after adjusting for age.

Association between polymorphisms in the XRCC1 gene and the risk of non-small cell lung cancer.

Here, we have reported a case-control study investigating the association between XRCC1 codons Arg194Trp, Arg280His, and Arg399Gln and the development of NSCLC. NSCLC patients (N = 245) and healthy controls (N = 257) were randomly selected from the Huaihe Hospital between March 2012 and August 2014. DNA extracted from the patient and control blood samples were subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to assess the genotyping of XRCC1 Arg194Trp, Arg280His, and Arg399Gln. Multivariate logistic regression analyses revealed an association between the expression of the AA genotype and A allele genotypes and a significantly increased risk of NSCLC, compared to the GG genotype [95% confidence interval (CI); Odd's ratio (OR) = 2.82 (1.141-5.86) and 1.67 (1.17-2.37), respectively]. The potential association between the A allele of XRCC1 Arg399Gln and the risk of NSCLC was more evident in smokers (95%CI; OR = 1.70; 1.11- 2.63). In conclusion, the XRCC1 Arg399Gln polymorphism was found to be associated with increased risk of NSCLC, especially in tobacco smokers.

Effect of X-ray repair cross complementing group 1 polymorphisms on the efficacy of platinum-based chemotherapy in patients with nonsmall cell lung cancer.

X-ray repair cross complementing group 1 (XRCC1) has been indicated to be correlated with the efficacy of platinum-based chemotherapy. But study results were still debatable. Thus, a meta-analysis was conducted. A literature search was performed using the PubMed, EMBASE, CNKI, with the databases being last accessed on November 24, 2014. Odds ratios with 95% confidence intervals were used to assess the strength of the association. In this meta-analysis, we found that XRCC1 Arg194Trp polymorphism was significantly associated with the efficacy of platinum-based chemotherapy. However, XRCC1 Arg399Gln polymorphism showed no impact on the efficacy of platinum-based chemotherapy. This meta-analysis suggested that the XRCC1 Arg194Trp polymorphism may be associated with efficacy of platinum-based chemotherapy. Further studies with a larger sample size are needed to further assess this result.

&lt;I&gt;XRCC1&lt;/I&gt; Arg194Trp and &lt;I&gt;XRCC1&lt;/I&gt; Arg399Gln Polymorphisms Affect Clinical Features and Prognosis of Myelodysplastic Syndromes

&lt;I&gt;XRCC1&lt;/I&gt; Arg194Trp and &lt;I&gt;XRCC1&lt;/I&gt; Arg399Gln Polymorphisms Affect Clinical Features and Prognosis of Myelodysplastic Syndromes

Association between XRCC1 Arg399Gln polymorphism and susceptibility to hepatocellular carcinoma in Chinese populations: A Meta-analysis

Association between XRCC1 Arg399Gln polymorphism and susceptibility to hepatocellular carcinoma in Chinese populations: A Meta-analysis

Association of Arg462Gln Polymorphism in RNASEL Gene With the Risk of Prostate CancerAmong Iranian Population

In the July issue of “Gene, Cell and Tissue”, R462Q Mutation in Prostate Cancer Specimens 1 investigated the effect of Arg462Gln polymorphism in sporadic prostate cancer patients among Iranian population. The study samples comprised of formalin fixed paraffin embedded specimen obtained from 51 histopathologically confirmed specimens from patients with prostate cancer and 70 from control individuals with non-cancerous prostate (prostatitis, hyperplasia). RNASEL Arg462Gln or G1385A polymorphism analysis performed using ARMS (Amplification Refractory Mutation System) PCR with allele specific primers were used to detect single-base substitution. This was followed by the association analysis between RNASEL genotype and prostate cancer. The authors could not find any significant association between the polymorphism and risk of disease. Few years back a worldwide epidemiological survey on prostate cancer revealed that it is the third leading causes of death in developed countries such as United States and emphasized that it is becoming a growing health concern in the developing nations as well 2. Like any other complex neoplastic disorder both genetic and non genetic factors interact in its development and progression 3. Age, ethnic background and family history are the three main epidemiological risk factors for this disease out of which family history is the strongest contributor. Based on family history, prostate cancer can be classified into sporadic, familial and hereditary. Hereditary predispositions are quite rare and contribute to less than 5% of the cases while familial cases account for 10-20% of cases. The rest are sporadic cases with typically only one person in their family who were diagnosed with the disease 4. Numerous studies have been conducted to identify the prostate cancer susceptibility genes using linkage analysis. Smith et al. identified the first susceptibility locus, designated as HPC1, which mapped to the long arm of chromosome 1 (1q24-25) (5), few years later, Carpten et al. reported RNASEL gene as one of the candidate for HPC1 (6). RNASEL is an endonuclease involving in apoptotic and antiviral activities of interferons. Along with truncating mutations in this gene, several missense variants were reported by Rokman et al. by screening the entire coding sequence of RNASEL using Single-strand conformation polymorphism (SSCP) (7). The Arg462Gln variant has a significant role in hereditary prostate cancer as the variant has three times less enzymatic activity compared to the wild genotype (8). They also reported that heterozygous individuals had double the risk of prostate cancer compared to the noncarrier cases with hereditary prostate cancer, but at the same time various studies did not find any association between sporadic prostate cancer and this variation in Caucasian and African American population (8, 9). The statistical analysis has been limited to unadjusted risk calculation. The risk calculation after adjustment to the age and clinical parameters would be a better approach. The control DNA was taken from hyperplastic prostate tissue so this tissue may not represent as a proper control sample. It is better to use DNA samples obtained from healthy individuals as the healthy control. Moreover the sample size is very small for any association study thus; a larger sample size is certainly warranted in future. Sometimes, ARMS PCR may produce incorrect genotypes, especially in homozygotes, so, it is better to recheck the genotypes by alternate sequencing methods. The authors did not find any association between Arg462Gln polymorphism and the risk of sporadic prostate cancer. Despite the limitations, this study is important as it may be first of its kind among Iranian population.