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RNASEL Gene Polymorphisms and the Risk of Prostate Cancer: a Meta-analysis

Authors' Affiliations: ¹ Biostatistics Unit, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre and ² Centre for Molecular Epidemiology and Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Requests for reprints: Huihua Li, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, 11 Hospital Drive, Singapore, Singapore 169610. Phone: 65-62369451; Fax: 65-65365503; E-mail: ctelhh{at}nccs.com.sg.

	Abstract

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
Purpose: Studies revealing conflicting results on the role of RNASEL polymorphisms Glu265X, Arg462Gln, and Asp541Glu on prostate cancer risk led us to perform a meta-analysis to investigate the association of these polymorphisms and prostate cancer risk.

Experimental Design: Relevant studies were selected by searching PubMed from January 1996 to August 2005 using keywords "RNASEL gene AND prostate cancer." For each study, odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the gene effect. Pooled estimates of the OR were computed using the random effects model.

Results: Ten studies were included in the meta-analysis. The overall results suggested no major influence of these variants on prostate cancer risk. However, analysis of the Asp541Glu polymorphism by ethnic populations showed that Asp/Glu (familial cases versus control: OR, 1.38; 95% CI, 1.04-1.82; sporadic cases versus control: OR, 1.26; 95% CI, 1.07-1.48; prostate cancer versus control: OR, 1.29; 95% CI, 1.12-1.48) and Asp/Glu + Glu/Glu (familial cases versus control: OR, 1.37; 95% CI, 1.10-1.70; sporadic cases versus control: OR, 1.24; 95% CI, 1.07-1.44; prostate cancer versus control: OR, 1.27; 95% CI, 1.13-1.44) increased prostate cancer risk in Caucasians, thus suggesting a dominant model for the Glu variant.

Conclusions: Compared with the genotype Asp/Asp, the Glu variant at the Asp541Glu polymorphism increases prostate cancer risk by <2-fold in Caucasians, regardless of family history of the disease. This suggests that genuine genetic effects of this polymorphism may account for only a part of prostate cancer in the Caucasian population.

Significant linkage between prostate cancer and chromosome 1q24-25, now denoted as HPC1, has been reported (8–10) and confirmed by the International Collaboration on Prostate Cancer Genetics, which pooled 772 families from nine international groups (11). One of the candidate genes within the HPC1 region is 2'-5'-oligoadenylate–dependent RNase L (RNASEL; MIM 601518 and 180435), which encodes a constitutively expressed latent endoribonuclease that mediates the antiviral and proapoptotic activities of the IFN-inducible 2-5A system. The linkage of HPC1 to RNASEL suggests that RNase L directly or indirectly suppresses one or more steps in prostate tumorigenesis and/or metastasis. The RNASEL gene has been implicated in prostate cancer susceptibility as a result of the first genome-wide linkage scan (8). The effect of Glu265X, Arg462Gln, and Asp541Glu of the RNASEL gene on prostate cancer risk has been reported but with conflicting conclusions. Only one study investigated the linkage disequilibrium of Glu265X, Arg462Gln, and Asp541Glu and found them to be in significant linkage disequilibrium (12).

Carpten et al. (13) detected nonsense mutation Glu265X in an index case of European ancestry and three of his affected brothers. Rökman et al. (14) reported a significantly higher mutation frequency of Glu265X in Finnish patients with hereditary prostate cancer than in controls, with the highest mutation frequency found in patients with four or more affected family members. In contrast, Wiklund et al. (12) and Maier et al. (15) did not find any evidence of difference in prostate cancer risk in Swedish and German populations, respectively.

Rökman et al. (14) also found a higher variant frequency at Arg462Gln in hereditary prostate cancer than in controls. Compared with Arg462 homozygotes, Casey et al. (16) found an increased risk among Gln462 homozygotes in discordant sibling pairs of Caucasian and African American descent. Rennert et al. (17) reported a significant increase in risk among African American harboring the genotype Arg/Gln + Gln/Gln with family history. Wang et al. (18) and Nakazato et al. (19) showed the protective effect of Gln/Gln in Caucasians and Japanese, respectively. However, there was no evidence of association between Arg462Gln and prostate cancer in Swedish and German populations, respectively (12, 15).

Nakazato et al. (19) reported that the Asp/Asp genotype of polymorphism Asp541Glu increased the familial prostate cancer risk in the Japanese population. Asp541Glu was also found among the Finnish (14), non-Hispanic Whites (18), Swedish (12), German (15), and European Americans (20). However, there was no difference in genotype distribution between the controls and cases.

Genetic mutations, such as Met1Ile in the African American (13), Gly59Ser and Ser406Phe in the Finnish (14), and 471delAAAG in the Ashkenazi (21, 22) were identified in RNASEL in addition to Glu265X, Arg462Gln, and Asp541Glu. However, only one or two studies investigated these mutations. Therefore, in this meta-analysis, we focused only on the Glu265X, Arg462Gln, and Asp541Glu polymorphisms and hypothesized that these variants of the RNASEL gene increase prostate cancer risk.

	Materials and Methods

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
Data collection. Relevant studies were selected by searching PubMed from January 1996 to August 2005 using the keywords "RNASEL gene AND prostate cancer." This resulted in a total retrieval of 25 articles.

We independently reviewed all studies for inclusion and recorded data from these studies consistently. Reference lists of the relevant articles were also hand-searched. The discrepancies in data extraction were resolved through consensus. Studies were included if any polymorphisms of Glu265X, Arg462Gln, or Asp541Glu of the RNASEL gene were investigated in both cases (hereditary prostate cancer, familial prostate cancer, or sporadic prostate cancer) and controls (healthy men).

Whenever possible, the following information was extracted from the publications: (a) odds ratio (OR) and 95% confidence interval (95% CI) comparing subjects with different genotypes at Glu265X, Arg462Gln, or Asp541Glu; (b) genotype distributions at any of these three polymorphisms for the cases and controls. In the latter, the ORs and 95% CIs were derived based on the genotype distribution in the cases and controls (23) if it is appropriate to assume that subjects in each case and control group are independent (12–15, 18, 24). When the ORs and 95% CIs for all cases were not available, these were estimated via meta-analysis using random effects model based on available ORs and 95% CIs for familial cases and sporadic cases (12, 18). Meta-analysis using random effects model was also used to estimate ORs and 95% CIs when comparing genotypes with at least one variant to wild type if ORs and 95% CIs were only available for separate variant homozygotes and heterozygotes (15, 16, 18–20). For data not provided in tabular form, the required information were extracted or estimated from the main text (13, 24), or obtained by contacting corresponding authors (12, 18), where possible.

Statistical methods. Begg's rank correlation test and Egger's regression asymmetry test were used to assess the existence of publication bias. In addition, the Duval and Tweedie nonparametric "trim and fill" method of accounting for publication bias was done to formalize the use of funnel plots and adjust the meta-analysis to incorporate the theoretical missing studies.

Forest plots and Q-statistics were used to investigate the degree of heterogeneity between studies. P < 0.1 was interpreted as evidence of heterogeneity among the combined studies than would be expected by chance alone.

Pooled estimates were reported using random effects models (DerSimonian-Laird method; ref. 25) as some analyses showed heterogeneity. Besides, the random effects model appropriately account for inter-study heterogeneity, such as differences in study design (e.g., population-based case-control versus family-based case-control) and clinical differences in study populations. We further did the analysis considering only Caucasian subjects to explore possible sources of observed heterogeneity between the combined studies. All analyses were done using STATA version 7 (Stata Corp., College Station, TX).

	Results

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
Of the 25 articles (all of case-control study design) identified, only 10 studies investigated the role of polymorphisms Glu265X, Arg462Gln, and Asp541Glu of the RNASEL gene on the risk of prostate cancer.

	Glu265X

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
Five studies (12–15, 24) were included in the meta-analysis on the relationship between polymorphism Glu265X and the risk of prostate cancer (Table 1 ).

None of the individual studies reported any difference in the risk of familial prostate cancer or prostate cancer when comparing the genotype Glu/X with Glu/Glu (Table 1). This is consistent with the results of the meta-analysis, which also showed no difference in risk of familial prostate cancer (OR, 1.67; 95% CI, 0.69-4.08) and all prostate cancers (OR, 1.04; 95% CI, 0.68-1.60).

Caucasian studies. Excluding the study by Chen et al. (24) when comparing genotypes Glu/Glu and Glu/X did not alter the risk of prostate cancer for Caucasians with family history (OR, 1.44; 95% CI, 0.62-3.36), without family history (OR, 0.97; 95% CI, 0.59-1.59), and all cases (OR, 1.01; 95% CI, 0.66-1.56).

	Arg462Gln

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
Seven studies (12, 14–19) were included in the meta-analysis involving the role of polymorphism Asp462Gln on the risk of prostate cancer (Table 2 ).

All prostate cancer. Compared with Arg/Arg, the subjects harboring the genotype Gln/Gln, Arg/Gln, or Arg/Gln + Gln/Gln showed no difference in the risk of prostate cancer (Table 2).

Sporadic prostate cancer. Casey et al. (16) reported an increased prostate cancer risk with the genotype Gln/Gln, Arg/Gln, and Arg/Gln + Gln/Gln in Caucasians and African Americans without family history of prostate cancer compared with Arg/Arg (Table 2). The results of the meta-analysis, however, showed no difference in the sporadic prostate cancer risk for Gln/Gln (OR, 1.09; 95% CI, 0.90-1.32), Arg/Gln (OR, 1.08; 95% CI, 0.92-1.28), and Arg/Gln + Gln/Gln (OR, 1.14; 95% CI, 0.97-1.34) genotypes.

Familial prostate cancer. Nakazato et al. (19) reported that the Gln/Gln genotype decreased familial prostate cancer risk in Japanese compared with Arg/Arg (Table 2). In contrast, the five Caucasian (including African Americans) studies did not report any difference in familial prostate cancer risk. The meta-analysis also showed no difference in risk between Gln/Gln and Arg/Arg genotypes for subjects with family history (OR, 0.58; 95% CI, 0.22-1.50). Although Rennert et al. (17) found an increased familial prostate cancer risk among African Americans harboring the Arg/Gln + Gln/Gln genotype, the meta-analysis found no difference in risk for Arg/Gln (OR, 0.93; 95% CI, 0.78-1.11) and Arg/Gln + Gln/Gln (OR, 0.87; 95% CI, 0.65-1.16).

Caucasian studies. Considering only the Caucasian studies (12, 14–18), the Q-statistic showed no evidence of heterogeneity comparing genotypes Gln/Gln and Arg/Arg, either between familial prostate cancer and control or between all prostate cancer and control (both P > 0.1). Thus, the presence of heterogeneity in the overall meta-analysis might be partly due to the inclusion of the Japanese who are ethnically different from the Caucasians. However, there was evidence of heterogeneity when genotypes Arg/Gln + Gln/Gln and Arg/Arg were compared in terms of sporadic prostate cancer risk (P = 0.064).

Only one study (16) found a significant difference in sporadic prostate cancer risk in Caucasians with the genotype Gln/Gln, Arg/Gln, and Arg/Gln + Gln/Gln compared with Arg/Arg. As such, the meta-analysis also did not show any difference in prostate cancer risk in Caucasians in these comparisons, regardless of family history of prostate cancer (Table 2).

	Asp541Glu

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
Six studies (12, 14, 15, 18–20), which investigated the effect of different genotypes at Asp541Glu on the risk of prostate cancer, were included in the meta-analysis (Table 3 ).

All prostate cancer. Compared with the Asp/Asp genotype, those harboring the Glu/Glu genotype were not at increased risk of prostate cancer (OR, 0.91; 95% CI, 0.53-1.56), disregarding family history of prostate cancer. There was also no difference in risk of prostate cancer comparing Asp/Glu + Glu/Glu versus Asp/Asp (OR, 0.95; 95% CI, 0.60-1.49).

Familial prostate cancer. The risk for Glu/Glu genotypes compared with Asp/Asp genotypes remained unaltered in subjects with family history of prostate cancer (OR, 0.86; 95% CI, 0.37-2.03). Except for Nakazato et al. (19), all other studies involving Caucasian subjects showed no evidence of difference in familial prostate cancer risk when comparing Glu/Glu with the Asp/Asp genotype. Similarly, no difference in familial prostate cancer risk was noted between subjects harboring the Asp/Glu + Glu/Glu and Asp/Asp genotypes (OR, 0.79; 95% CI, 0.29-2.17).

Caucasian studies. The Q-statistic did not show any heterogeneity in the meta-analysis of Caucasian studies (all P > 0.1). The heterogeneity in the overall meta-analysis might be due to the inclusion of the Japanese subjects.

All prostate cancer. Wang et al. (18) reported that the Asp/Glu or Asp/Glu + Glu/Glu genotype confers a higher risk of prostate cancer in Caucasians compared with Asp/Asp, regardless of family history (Table 3). This finding is confirmed by the random effects model, which also showed an elevated risk of prostate cancer for Asp/Glu and Asp/Glu + Glu/Glu (Table 3). Although none of the studies showed an increased risk with Glu/Glu, this phenomenon was noted in the meta-analysis comprising Caucasians, regardless of family history of prostate cancer (OR, 1.19; 95% CI, 1.02-1.39).

Sporadic prostate cancer. For those without family history of prostate cancer, the pooled analysis showed that subjects harboring the Asp/Glu or Asp/Glu + Glu/Glu genotypes tended to have a higher risk of prostate cancer than the Asp/Asp genotype, with estimated OR of 1.26 (95% CI, 1.07-1.48) and 1.24 (95% CI, 1.07-1.44) respectively. However, in keeping with the result of individual studies, the meta-analysis showed no difference in the risk of sporadic prostate cancer between subjects harboring the genotypes Glu/Glu and Asp/Asp (OR, 1.16; 95% CI, 0.97-1.39).

Familial prostate cancer. As in Wang et al. (18), the meta-analysis suggested that subjects harboring at least one variant of Glu tended to have a higher risk of familial prostate cancer (Asp/Glu versus Asp/Asp: OR, 1.38; 95% CI, 1.04-1.82; Asp/Glu + Glu/Glu versus Asp/Asp: OR, 1.37; 95% CI, 1.10-1.70). However, it showed no difference in familial prostate cancer risk when comparing Glu/Glu versus Asp/Asp genotypes (OR, 1.27; 95% CI, 0.98-1.64), in keeping with the results of individual study (Table 3).

	Discussion

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
This meta-analysis examined polymorphisms Glu265X, Arg462Gln, and Asp541Glu of the RNASEL gene in their relationship with prostate cancer susceptibility.

No evidence of changed prostate cancer risk was found in subjects with X variant of Glu265X polymorphism. Given the relative rarity of this variant on a population basis, larger studies with many thousands of subjects would be needed to confirm this result.

Although the RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases, with three times less enzymatic activity than the wild type, and has been found to be associated with sporadic prostate cancer risk among Caucasians and African Americans (16) and with familial prostate cancer risk among African Americans (17), our analyses did not find such an association. However, the only Asian study (19) found decreased familial prostate cancer risk in the Japanese with the genotype Gln/Gln. Larger studies involving a wider spectrum of Asian people are needed for a more definitive evaluation of the relationship between Arg462Gln polymorphism and prostate cancer risk among Asians.

The result of the meta-analysis suggests that genotypes with Glu variant in the Asp541Glu polymorphism increase modestly the risk of prostate cancer in Caucasian subjects, regardless of family history, with a magnitude of the effect that is unlikely to be >2-fold as judged by the upper 95% limits of the CIs. Although Nakazato et al. (19) reported a protective effect of the Glu variant at the Asp541Glu polymorphism among the Japanese, further studies should be carried out to confirm such an effect in the Asian populations.

Our analyses suggest that genotype, more than family history, is associated with the risk of prostate cancer. However, our results show that the mutation of Asp541Glu contributes only a part to the overall prostate cancer susceptibility among Caucasians, although Asp541Glu produced similar levels of RNase L activity as wild type enzyme (26). If we assume a risk ratio of 1.3 and a proportion of 0.8 among the subjects with variant Glu at this polymorphism, the population attributable risk percentage for prostate cancer in association with this variant would be 19.4%.

Other limitations of this meta-analysis should be acknowledged. First, nondifferential misclassification bias is possible because the majority of the studies did not consider that some controls might have developed prostate cancer in subsequent years. However, as the lifelong risk of prostate cancer among the Americans (with the highest incidence rate) is only about 16% (27), the OR dilution would probably be small.

Second, some studies include only the index case in each family with family history of prostate cancer (13–15), whereas others include more than one case. Such heterogeneity in study design result in different estimation procedures for the risk estimates, as intra-subject correlation has to be accounted for especially in studies that include more than one case in a family.

There is also clinical heterogeneity in the definition of cases across studies. For example, the prostate-specific antigen level for 50% of cases was <7 ng/mL in three studies (16, 17, 24) and <9.9 ng/mL in Wang et al. (18), whereas that for all cases was >50 ng/mL in Noonan-Wheeler et al. (20). This resulted in the latter that recruited only patients with aggressive prostate cancer, in contrast with other studies that recruited 40% of cases with advanced prostate cancer (12), or 25% of cases with stage T₃/T₄ prostate cancer (17, 18). Separate sensitivity analyses were conducted to exclude the study with aggressive disease (20) and include those with <50% of patients with advanced prostate cancer (12, 17, 18). These results were largely consistent with the meta-analysis, which included all studies. The severity of disease did not seem to have as great an effect on the effect of these polymorphisms as would have been expected.

In our analysis of the relationship between RNASEL gene polymorphisms and sporadic prostate cancer risk, a small proportion of cases with family history were included (14, 20) because it is not feasible to separate the familial cases from the sporadic cases based on the available information. For example, Although Rökman et al. (14) considered 9.6% unselected patients, and Noonan-Wheeler et al. (20) included 25% cases with a positive family history of prostate cancer, sensitivity analysis of the Asp541Glu polymorphism excluding these two studies showed that the risk of prostate cancer among subjects without family history of prostate cancer was not materially altered.

Furthermore, different studies used different criteria to define familial cases. Some studies (15, 18, 19, 24) recruited familial cases with at least two affected family members. Noonan-Wheeler et al. (20) recruited familial cases with at least one affected first-degree or second-degree relative, whereas Rennert et al. (17) recruited only those with at least one affected first-degree relative. Due to the limited number of studies with familial cases, we consider cases as familial cases whenever they have one relative with prostate cancer. Nevertheless, imposing a more stringent criterium by considering at least two affected family members, for example, did not lead to a different conclusion.

To appropriately account for such heterogeneity between studies, we implemented the random effects model. The Duval and Tweedie nonparametric "trim and fill" method was adopted to adjust for publication bias. Meta-analysis with and without "trim and fill" method did not draw different conclusion, indicating that our results are statistically robust.

Postulated genetic associations for prostate cancer need to be carefully validated across several studies because early and small genetic association studies may result in spurious findings (28–30). As shown by our meta-analyses, genetic associations for such a multigenetic disease are likely to have relatively small ORs, thus requiring larger sample sizes to have sufficient power to detect an association.

	Conclusions

Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 
In conclusion, among the polymorphisms of Glu265X, Arg462Gln, and Asp541Glu, this meta-analysis finds some evidence that the Asp541Glu polymorphism is associated with an increased risk of prostate cancer in Caucasians. However, it is unlikely that this mutation confers more than a 2-fold increase in risk of prostate cancer. As studies among the Asians are currently limited, further studies including a wider spectrum of Asian subjects should be carried out to investigate the role of these RNASEL variants in the Asian population.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/22/05; revised 5/21/06; accepted 6/28/06.

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Top Abstract Materials and Methods Results Glu265X Arg462Gln Asp541Glu Discussion Conclusions References

 

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