Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer: a case-control study

BACKGROUND: RNASEL is thought to be a susceptibility gene for hereditary prostate cancer and encodes the endoribonuclease RNase L, which has a role in apoptosis and is a candidate tumour-suppressor protein. A common sequence variation in RNASEL, Arg462Gln, has been associated with hereditary and sporadic prostate cancer, and the Gln variant has about three-fold reduced RNase activity in vitro. In view of the association between the age of onset of hereditary non-polyposis colorectal cancer and functionally different variants of P53, which play a key part in the apoptotic pathway, we aimed to assess whether the Arg462Gln variation of RNASEL affects the age of onset of hereditary non-polyposis colorectal cancer. METHODS: We screened 251 patients with hereditary non-polyposis colorectal cancer who were unrelated, had pathogenic germline mutations in MSH2 (n=141) or MLH1 (n=110), and had colorectal carcinoma as the first tumour, for variation at codon 462 of RNASEL and compared them with 439 healthy controls. FINDINGS: The median age of onset was 40 years (range 17-75) for patients with an Arg/Arg genotype at codon 462, 37 years (13-69) for patients with an Arg/Gln genotype, and 34 years (20-49) for those with a Gln/Gln genotype (p=0.0198). Only the RNASEL genotype had a significant effect on age of onset (p=0.0062) in an additive mode of inheritance. Pair-wise comparisons between genotype groups showed that the two homozygous groups (ie, Arg/Arg vs Gln/Gln) differed significantly in age of disease onset (mean age difference 4.8 years [SD 1.7], p=0.0044). INTERPRETATION: A sequence variation in the prostate-cancer-susceptibility gene RNASEL has a role in a different, unassociated malignant disease. Genotypes at RNASEL codon 462 are associated with age of onset of hereditary non-polyposis colorectal cancer in a dose-dependent way, and might have a role in preventive strategies for this disease.     

Trans-fatty acid intake and increased risk of advanced prostate cancer: modification by RNASEL R462Q variant

Previous studies have examined the role of higher trans-fatty acid consumption on prostate cancer risk, but the results remain unclear. Any potential association may be modified by variants in genes involved with immune and inflammatory responses. To investigate this, we undertook a case-control study (N = 1012) of the association between trans-fatty acid intake and advanced prostate cancer, and evaluated whether this effect was modified by a functional polymorphism in the RNASEL gene (R462Q). Among Caucasians (N = 834), we observed that each type of trans-fatty acid and total trans-fatty acid intake showed a statistically significant positive association with prostate cancer, but only weakly increased risk for the isomers of cis-fatty acids. Compared with the lowest quartile of total trans-fatty acid consumption, the higher quartiles gave odds ratios (ORs) equal to 1.58 [95% confidence interval (CI): 1.00, 2.48], 1.95 (95% CI: 1.20, 3.19) and 2.77 (95% CI: 1.60, 4.79) (P-trend = 0.0003); this effect was modified by the RNASEL R462Q polymorphism (P(interaction) = 0.01). Among men with the QQ/RQ genotype, the association between total trans-fatty acid intake and prostate cancer was substantially stronger [ORs of higher quartiles equal to 2.93 (95% CI: 1.62, 5.30), 3.13 (95% CI: 1.64, 5.98) and 4.80 (95% CI: 2.29, 10.08), respectively]. For men with the RR genotype, total trans-fatty acid intake was not associated with disease. This suggests that among Caucasians, positive association between higher trans-fatty acid consumption and prostate cancer may be modified by the functional RNASEL variant R462Q.     

Assessment of the association between XRCC1 Arg399Gln polymorphism and lung cancer in Chinese

X-ray repair cross-complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base excision repair and plays an important role in the maintenance of genomic integrity. Polymorphisms in XRCC1 may alter the function and repair capacity of XRCC1 protein which further results in the genetic instability and lung carcinogenesis. Previous studies investigating the relationship between XRCC1 Arg399Gln polymorphism and lung cancer risk in Chinese yielded contradictory results. A meta-analysis was performed to clarify the effect of XRCC1 Arg399Gln polymorphism on lung cancer. The association was assessed by calculating the pooled odds ratio (OR) with 95 % confidence intervals (95 %CI). Nineteen studies with a total of 12,835 participants were included into this meta-analysis. Overall, there was an obvious association between XRCC1 Arg399Gln polymorphism and increased risk of lung cancer under three genetic models (Gln vs. Arg: OR?=?1.13, 95 %CI 1.01–1.25, P?=?0.029; GlnGln vs. ArArg: OR?=?1.41, 95 %CI 1.07–1.84, P?=?0.013; GlnGln vs. ArArg/ArgGln: OR?=?1.37, 95 %CI 1.07–1.76, P?=?0.013). Meta-analysis of 18 studies with high quality also found that there was an obvious association between XRCC1 Arg399Gln polymorphism and increased risk of lung cancer under three genetic models. There was no obvious risk of bias in the meta-analysis. Data from the current meta-analysis support the obvious association between XRCC1 Arg399Gln polymorphism and increased risk of lung cancer in Chinese.     

An updated meta-analysis between the association of XRCC1 Arg399Gln polymorphism and hepatocellular carcinoma risk

Background: Various studies have evaluated the relationship between X-ray repair cross-complementinggroup 1 (XRCC1) Arg399Gln polymorphism and hepatocellular carcinoma (HCC) risk, but the conclusionshave been inconsistent and underpowered. The purpose of this updated meta-analysis was to examine whetherXRCC1 Arg399Gln polymorphism confers susceptibility to HCC. Methods: Eligible studies extracted fromPubMed, Embase, Cochrane Library, VIP (chinese) and CNKI (chinese) up to November 2013 were included inthe study. Pooled odds ratio (OR) together with their 95% confidence interval (CI) were estimated to evaluateXRCC1 Arg399Gln polymorphism and HCC risk. Results: Finally, 21 studies with 4,170 cases and 5,030controls were involved in our meta-analysis. The results demonstrated that there was significant associationbetween Arg399Gln polymorphism and HCC risk under two contrast models in overall populations (AG vs GG:OR=1.265, 95%CI=1.036-1.545, p=0.021; AA+AG vs GG: OR=1.240, 95%CI=1.021-1.506, p=0.030). In subgroupanalyses, significant association was found in Asians (A vs G: OR=1.175, 95%CI=1.013-1.362, p=0.033; AG vsGG: OR=1.317, 95%CI=1.070-1.622, p=0.009; AA+AG vs GG: OR=1.289, 95%CI=1.055-1.575, p=0.013) andCaucasians (A vs G: OR=0.591, 95%CI=0.361-0.966, p=0.036; AA+AG vs GG: OR=0.468, 95%CI=0.234-0.934,p=0.031). Conclusions: The results suggest that XRCC1 Arg399Gln polymorphism may increase HCC riskespecially among Asians. However, XRCC1 Arg399Gln polymorphism might act as a protective role againstHCC among Caucasians.     

Lack of an association between the TGFBR1*6A variant and colorectal cancer risk.

PURPOSE: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies. EXPERIMENTAL DESIGN: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted. RESULTS: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A. CONCLUSION: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.     

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR)=1.47, 95% confidence interval (95% CI)=1.04-2.06, p=0.03) in a dose-dependent manner (ptrend=0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR=1.48, 95% CI=1.10-1.99, p=0.009; ptrend=0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR=4.11, 95% CI=1.27-13.31, p=0.011).     

Assessment of the association between XRCC1 Arg399Gln polymorphism and glioma susceptibility

The Arg399Gln polymorphism, located in the region of the BRCT-I interaction domain of XRCC1, has been extensively explored in its function and association with glioma risk. However, these studies generated contradictory instead of conclusive results. A meta-analysis was performed to derive a more precise evaluation of the relationship between XRCC1 Arg399Gln polymorphism and glioma risk. We searched the PubMed, EMBASE, and Web of Science and extracted 12 eligible studies with 4,062 glioma cases and 5,302 glioma-free controls for this meta-analysis. The pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to assess the strength of the association. In the overall analysis, we found that the XRCC1 Arg399Gln polymorphism was statistically associated with the risk of glioma (OR_{GG vs. AG + AA}?=?0.90, 95 % CI?=?0.84–0.97, P _{heterogeneity}?=?0.020; OR_{allele G vs. allele A}?=?0.96, 95 % CI?=?0.91–1.00, P _{heterogeneity}?=?0.110). We also observed significant association between this polymorphism and glioma risk in Asian populations. The results of the meta-analysis suggest a potential decreased susceptibility to glioma in association with the XRCC1 Arg399Gln polymorphism, especially in Asians. Yet, it is necessary to conduct future prospective explorations to gain a better insight into the impact of XRCC1 Arg399Gln polymorphism on glioma risk.     

XRCC1 Arg399Gln基因多态性与中国人群肝细胞癌易感性的Meta分析

目的 探讨XRCC1 Arg399Gln基因多态性与肝细胞癌（HCC）易感性的关系。方法 计算机检索PubMed、中国生物医学文献（CBM）、中国知网、万方及维普等数据库,收集有关XRCC1 Arg399Gln基因多态性与HCC易感性关系的病例对照研究,提取纳入文献的相关数据进行Meta分析,以病例组与对照组XRCC1 Arg399Gln各种基因模型的比值比（OR）为效应指标,发表偏倚采用Eggers检验和Beggs检验。结果 共17篇文献符合纳入标准,累计病例数3301例,对照组4156例。XRCC1 Arg399Gln基因多态性与中国人群HCC易感性有明显关联性（G/G vs. A/A：OR=1.32,95％CI：1.13～1.54,P=0.000;A/G vs. A/A：OR=1.25,95％CI：1.10～1.41,P=0.000;A/G+G/G vs. A／A：OR=1.22,95％CI：1.09～1.36,P=0000;G／G vs. A／A+A／G：OR=1.20,95％CI：1.04～1.39,P=0.014）。根据健康对照组来源不同的亚组分析中,所有地区或者控制人口来源医院的研究结果均显示,XRCC1 Arg399Gln 基因多态性与HCC易感性有明显关联性,但控制人口非医院来源的研究结果显示XRCC1 Arg399Gln 基因多态性与HCC易感性无明显关联性;根据地区不同分组的亚组分析中,在广西地区,除隐性遗传模型外（G/G vs. A/A+A/G：OR=1.25,95％CI：0.95～1.65,P=0.115）,其余遗传模型结果显示XRCC1 Arg399Gln基因多态性与广西地区HCC易感性有明显相关性（G/G vs. A/A：OR=1.47,95％CI：1.10～1.95,P=0.009;A/G vs. A/A：OR=1.35,95％CI：1.17～1.56,P=0.000;A/G+G/G vs.A／A：OR=133,95％CI：1.16～1.52,P=0.000）。结论 XRCC1 Arg399Gln 基因多态性可能增加中国人群HCC的易感性,尤其在广西地区。     

The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1

p53 and the prostate-cancer-susceptibility gene RNASEL are tumour suppressor genes involved in apoptosis. We have previously reported that the common, functionally different variants Arg72Pro in p53 and Arg462Gln in RNASEL are associated with the age of disease onset of colorectal cancer in Lynch syndrome patients. To assess the combined effect of both variants, we screened 246 unrelated Lynch syndrome patients with a pathogenic germline mutation either in MSH2 (n=138) or in MLH1 (n=108) and colorectal cancer as first tumour, and 245 healthy controls. The global log rank test revealed significant differences in the age of disease onset for the genotypes of each variant (p=0.0176 for p53 and p=0.0358 for RNASEL) and for the combined genotypes of both variants (p=0.0174). The highest difference in median age of disease onset was seen between homozygotes for the wild-types in both genes (42years [range 22-75]) and homozygotes for the variant alleles in both genes (30years [range 26-47]). A multivariate Cox regression model indicated that only the p53 and RNASEL genotypes had a significant influence on age of disease onset (p=0.016 for p53 and p=0.014 for RNASEL) in an additive mode of inheritance, and that the effects of both variants are purely additive, which supports the notion that the p53 and RNaseL pathways do not interact. These findings may be relevant for preventive strategies in Lynch syndrome.     

XRCC1 Arg399Gln gene polymorphism and breast cancer risk: a meta-analysis based on case-control studies

Background: The Arg399Gln polymorphism in the XRCC1 DNA repair gene is likely to be involved with the development of breast cancer (BC). However, there have been inconsistent reports of association. The objective of this study was to systematically evaluate the published papers. Methods: We performed a meta-analysis of 44 published case-control studies fitting our eligibility criteria. These studies involved XRCC1 Arg399Gln polymorphisms in 20,841 BC cases and 22,688 controls in dominant (GlnGln+ArgGln vs. ArgArg), recessive (GlnGln vs. ArgGln+ArgArg), and co-dominant (GlnGln vs. ArgArg) inheritance models. Analyses of Asian, African and Caucasian ethnic subgroups was also conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Results: Our overall analyses indicated Arg399Gln to be associated with a trend of increased BC risk when using recessive (OR=1.15, 95%CI: 1.05–1.27), and co-dominant models (OR=1.15, 95%CI: 1.04-1.27) to analyze the data. In ethnic subgroups, Arg399Gln significantly increased BC risk in Asians (OR=1.54, 95%CI: 1.18–2.01) when using recessive model analysis, in Africans (OR=1.30, 95%CI: 1.07–1.60) when using dominant model analysis, and in Asians (OR=1.50, 95%CI: 1.15–1.97) and Africans (OR=1.80, 95%CI: 1.08-3.02) when using the co-dominant model analysis. Conclusions: From our meta-analysis of data from 44 publications, we conclude that XRCC1 Arg399Gln allele is a risk factor for the development breast cancer, especially among Asian and African populations.     

Leptin receptor Gln223Arg polymorphism and breast cancer risk in Nigerian women: A case control study

Background  

Leptin, a 16 kDa polypeptide hormone, implicated in various physiological processes, exerts its action through the leptin receptor, a member of the class I cytokine receptor family. Both leptin and leptin receptor have recently been implicated in processes leading to breast cancer initiation and progression in animal models and humans. An A to G transition mutation in codon 223 in exon 6 of the leptin receptor gene, resulting in glutamine to arginine substitution (Gln223Arg), lies within the first of two putative leptin-binding regions and may be associated with impaired signaling capacity of the leptin receptor. This study was designed to assess the role of this polymorphism in breast cancer susceptibility in Nigerian women.     

A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer.

XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA base damage and strand breaks. A common polymorphism (Arg-->Gln) at codon 399 of the XRCC1 gene has been previously linked to functional changes of the gene product and risk of cancers. We evaluated the association between XRCC1 Arg399Gln polymorphism and breast cancer risk in the population-based Shanghai Breast Cancer Study involving 1088 cancer patients and 1182 community controls. Genomic DNA from peripheral blood was used in genotyping assays, and exposure information and anthropometrics were collected through in-person interview. Plasma estrogen and sex hormone-binding globulin (SHBG) levels were measured for 190 postmenopausal breast cancer patients who had donated a pretreatment blood sample and 407 postmenopausal controls. Conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting potential confounders. Approximately 27% of controls carried the variant allele (Gln), and cases and controls had a similar distribution for both allele type and genotype of this polymorphism. We found that 7.8% of cases and 6.3% of controls were homozygous for the variant allele, resulting in an OR of 1.20 (95% CI, 0.85-1.69). The OR was slightly higher among younger women [<45 years of age (OR, 1.39; 95% CI, 0.82-2.36)] than older women [> or = 45 years of age (OR, 1.07; 95% CI, 0.68-1.67)], but neither OR was statistically significant. No modifying effect of major breast cancer risk factors, including years of menstruation, body mass index, waist:hip ratio, and blood estrogen levels, was noted. Homozygosity for the variant Gln allele was associated with an elevated risk of postmenopausal breast cancer among subjects with a higher blood level of SHBG (OR, 3.27; 95% CI, 1.16-9.20) and a reduced risk among those with a lower level of SHBG (OR, 0.60; 95% CI, 0.18-1.97). The overall results of the study suggest that Arg399Gln polymorphism of the XRCC1 gene alone may not play a substantial role in the risk of breast cancer among Chinese women.     

Lack of association between weight and oestrogen receptors in women with breast cancer

Evidence for a relationship between body weight and tumour oestrogen receptor (ER) level has been sought in women with newly diagnosed breast cancer. There was no significant correlation between body weight and tumour ER concentration, either over the whole range of observed weight or when considering groups above or below a weight of 68 kg. Similarly, when women were subgrouped by prognostic variables such as nodal status, tumour size, or menopausal status, there was no significant relationship between ER level and body weight. These data suggests that observations linking breast cancer risk with increasing body weight cannot be explained by variations in ER level.     

An association between XPC Lys939Gln polymorphism and the risk of bladder cancer: a meta-analysis

The polymorphism Lys939Gln in xeroderma pigmentosum complementation group C (XPC) gene has been reported to be associated with bladder cancer in some studies, though the results remain inconclusive. To explore this relationship between XPC Lys939Gln polymorphism and the susceptibility for bladder cancer and the impact of smoking exposures, a cumulative meta-analysis was performed in this study. PubMed and EMBASE databases have been systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between XPC Lys939Gln polymorphism and susceptibility to bladder cancer (BC). Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated. Thirteen studies were chosen in this meta-analysis, involving 4,927 BC cases (1,119 Asian, 2,670 Caucasian, and 1,138 mixed) and 5,185 controls (1,399 Asian, 2,629 Caucasian, and 1,157 mixed). The XPC 939Gln allele was significantly associated with increased risk of BC based on allelic contrast (OR?=?1.11, 95 % CI?=?1.02–1.21), homozygote comparison (OR?=?1.35, 95 % CI?=?1.08–1.68), and a recessive genetic model (OR?=?1.36, 95 % CI?=?1.09–1.68). The results from the present meta-analysis indicated that the 939Gln polymorphism in XPC is a risk factor for bladder carcinogenesis. Further large and well-designed studies are needed to confirm this conclusion.