RNase L Research Articles

Carriage of ELAC2 and RNASEL Genes and Risk Factors in Patients With Prostate Cancer in Burkina Faso

Carriage of ELAC2 and RNASEL Genes and Risk Factors in Patients With Prostate Cancer in Burkina Faso

Inhibition of phosphodiesterase 12 results in antiviral activity against several RNA viruses including SARS-CoV-2.

The 2',5'- oligoadenylate synthetase (OAS) - ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses. A library of 18 000 small molecules was screened for PDE12 inhibitor activity using a fluorescent probe specific for PDE12. The lead compounds (CO-17 or CO-63) were tested in cell-based antiviral assays using encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), dengue virus (DENV), West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro. Cross reactivity of PDE12 inhibitors with other PDEs and in vivo toxicity were measured. In EMCV assays, CO-17 potentiated the effect of IFNα by 3 log10. The compounds were selective for PDE12 when tested against a panel of other PDEs and non-toxic at up to 42 mg kg-1 in rats in vivo. Thus, we have identified PDE12 inhibitors (CO-17 and CO-63), and established the principle that inhibitors of PDE12 have antiviral properties. Early studies suggest these PDE12 inhibitors are well tolerated at the therapeutic range, and reduce viral load in studies of DENV, HCV, WNV and SARS-CoV-2 in human cells and WNV in a mouse model.

The Ability of Postimmunobiotics from L. rhamnosus CRL1505 to Protect against Respiratory Syncytial Virus and Pneumococcal Super-Infection Is a Strain-Dependent Characteristic.

Previously, we demonstrated that the non-viable strain Lacticaseibacillus rhamnosus CRL1505 (NV1505) or its purified peptidoglycan (PG1505) differentially modulated the respiratory innate antiviral immune response triggered by Toll-like receptor (TLR)-3 activation in infant mice, improving the resistance to primary respiratory syncytial virus (RSV) infection and secondary pneumococcal pneumonia. In this work, we evaluated the effect of other non-viable L. rhamnosus strains and their peptidoglycans on the respiratory immune response and their impact on primary and secondary respiratory infections. In addition, the duration of the protective effect induced by NV1505 and PG1505 as well as their ability to protect against different Streptococcus pneumoniae serotypes were evaluated. Our results showed that among the five selected L. rhamnosus strains (CRL1505, CRL498, CRL576, UCO25A and IBL027), NV1505 and NVIBL027 improved the protection against viral and pneumococcal infections by modulating the respiratory immune response. Of note, only the PG1505 presented immunomodulatory activities when compared with the other purified peptidoglycans. Studies on alveolar macrophages showed that NV1505 and PG1505 differentially modulated the expression of IL-6, IFN-γ, IFN-β, TNF-α, OAS1, RNAseL and IL-27 genes in response to RSV infection, and IL-6, IFN-γ, IL-1β, TNF-α, CCL2, CXCL2, CXCL10 and IL-27 in response to pneumococcal challenge. Furthermore, we demonstrated that NV1505 and PG1505 treatments protected mice against secondary pneumococcal pneumonia produced by different serotypes of S. pneumoniae until 30 days after stimulation with poly(I:C). This work advances the characterization of the protective effect of NV1505 and PG1505 by demonstrating that they increase resistance against the pneumococcal serotypes 3, 6B, 14 and 19F, with an effect that lasts up to 30 days after the primary viral inflammation. The results also confirm that the immunomodulatory properties of NV1505 and PG1505 are unique and are not shared by other members of this species, and suggest the existence of a capacity to stimulate trained immunity in alveolar macrophages.

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation.

Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma incidence and survival. Thus, we explored the effects of testosterone and 17β-estradiol on RNASEL and miR-146a expression in LM-20 and A375 melanoma cell lines. Direct targeting of miR-146a to the 3′ untranslated region (3′UTR) of RNASEL was examined using a luciferase reporter system. Our results indicate that RNASEL is a direct target of miR-146a in both melanoma cell lines. Trough qPCR and western blot analyses, we explored the effect of miR-146a mimic transfection in the presence of each hormone either on RNASEL mRNA level or on protein expression of RNase-L, the enzyme codified by RNASEL gene. In the presence of testosterone or 17β-estradiol, miR-146a overexpression did not influence RNASEL transcript level in LM-20 cell line, but it slightly induced RNASEL mRNA level in A375 cells. Remarkably, miR-146a overexpression was able to repress the protein level of RNase-L in both LM-20 and A375 cells in the presence of each hormone, as well as to elicit high expression levels of the activated form of the extracellular signal-regulated kinases (ERK)1/2, hence confirming the pro-tumorigenic role of miR-146a overexpression in melanoma. Thereafter, we assessed if the administration of each hormone could affect the endogenous expression of RNASEL and miR-146a genes in LM-20 and A375 cell lines. Testosterone exerted no significant effect on RNASEL gene expression in both cell lines, while 17β-estradiol enhanced RNASEL transcript level at least in LM-20 melanoma cells. Conversely, miR-146a transcript augmented only in the presence of testosterone in either melanoma cell line. Importantly, each hormone acted quite the opposite regarding the RNase-L protein expression, i.e., testosterone significantly decreased RNase-L expression, whereas 17β-estradiol increased it. Overall, the data show that, in melanoma cells treated with 17β-estradiol, RNase-L expression increased likely by transcriptional induction of its gene. Testosterone, instead, decreased RNase-L expression in melanoma cell lines with a post-transcriptional mechanism in which miR-146a could play a role. In conclusion, the pro-tumor activity of androgen hormone in melanoma cells could be exacerbated by both miR-146a increase and RNase-L downregulation. These events may contribute to the worse outcome in male melanoma patients.

Multi-gene panel testing increases germline predisposing mutations' detection in a cohort of breast/ovarian cancer patients from Southern Italy.

Breast cancer is the most common neoplasia in females worldwide, about 10% being hereditary/familial and due to DNA variants in cancer-predisposing genes, such as the highly penetrant BRCA1/BRCA2 genes. However, their variants explain up to 25% of the suspected hereditary/familial cases. The availability of NGS methodologies has prompted research in this field. With the aim to improve the diagnostic sensitivity of molecular testing, a custom designed panel of 44 genes, including also non-coding regions and 5’ and 3’ UTR regions, was set up. Here, are reported the results obtained in a cohort of 64 patients, including also few males, from Southern Italy. All patients had a positive personal and/or familial history for breast and other cancers, but tested negative to routine BRCA analysis. After obtaining their written informed consent, a genomic DNA sample/patient was used to obtain an enriched DNA library, then analyzed by NGS. Sequencing data analysis allowed the identification of pathogenic variants in 12 of tested patients (19%). Interestingly, MUTYH was the most frequently altered gene, followed by RNASEL, ATM, MSH6, MRE11A, and PALB2 genes. The reported resultsreinforce the need for enlarged molecular testing beyond BRCA genes, at least in patients with a personal and familial history, strongly suggestive for a hereditary/familial form. This gives also a hint to pursue more specific precision oncology therapy.

Simultaneous Onset of Pediatric Systemic Lupus Erythematosus in Twin Brothers: Case Report

There are hundreds of twin adult patients with systemic lupus erythematosus (SLE), but male children with SLE are rarely affected. Two monozygotic twin brothers developed SLE at the age of 11 years during 1 month. The index brother manifested with Henoch-Shonlein purpura, accompanied by ANA positivity, and later developed critical left femoral arterial stenosis with high levels of anti-dsDNA, antiphospholipid antibodies, hypocomplementemia, and Coombs-positive hemolytic anemia. At that time his twin brother had only identical autoimmune findings and developed clinical manifestation (myositis and fasciitis) a month later. Both twins had increased IFN-score and shared a heterozygous variant in the RNASEL gene. Index patients developed scalp rash and nephritis 6 months after their parents refused the treatment which has been lasted for 1 year after disease diagnostics.ConclusionThe simultaneous onset of the pediatric SLE in the male twin is a very rare situation suspected monogenic origin of the disease. Further functional studies are required to confirm the causative role of the mutation.

Carriage of mutations R462Q (rs 486907) and D541E (rs 627928) of the RNASEL gene and risk factors in patients with prostate cancer in Burkina Faso

BackgroundProstate cancer (Pca) is a public health problem that affects men, usually of middle age or older. It is the second most common cancer diagnosed in men and the fifth leading cause of death. The RNASEL gene located in 1q25 and identified as a susceptibility gene to hereditary prostate cancer, has never been studied in relation to prostate cancer in Burkina Faso. The aim of this study was to analyze the carriage of RNASEL R462Q and D541E mutations and risks factors in patients with prostate cancer in the Burkina Faso.MethodsThis case–control study included of 38 histologically diagnosed prostate cancer cases and 53 controls (cases without prostate abnormalities). Real-time PCR genotyping of R462Q and D541E variants using the TaqMan® allelic discrimination technique was used. Correlations between different genotypes and combined genotypes were investigated.ResultsThe R462Q variant was present in 5.3% of cases and 7.5% of controls. The D541E variant was present in 50.0% of cases and 35% of controls. There is no association between R462Q variants (OR = 0.60; 95%IC, 0.10–3.51; p = 0.686) and D541E variants (OR = 2.46; 95%IC, 0.78–7.80; p = 0.121) and genotypes combined with prostate cancer. However, there is a statistically significant difference in the distribution of cases according to the PSA rate at diagnosis (p ˂ 0.001). For the Gleason score distribution, only 13.2% of cases have a Gleason score greater than 7. There is a statistically significant difference in the Gleason score distribution of cases (p ˂ 0.001).ConclusionsThese variants, considered in isolation or in combination, are not associated with the risk of prostate cancer.

Mechanistic insights into non-coding Y RNA processing

ABSTRACT Y RNAs (84–112 nt) are non-coding RNAs transcribed by RNA polymerase III and are characterized by a distinctive secondary structure. Human Y RNAs interact with the autoimmune proteins SSB and RO60 that together form a ribonucleoprotein (RNP) complex termed RoRNP and Y RNAs also perform regulatory roles in DNA and RNA replication and stability, which has major implications for diseases including cancer. During cellular stress and apoptosis, Y RNAs are cleaved into 3’ and 5’ end fragments termed Y RNA-derived small RNAs (ysRNAs). Although some ysRNA functions in stress, apoptosis and cancer have been reported, their fundamental biogenesis has not been described. Here we report that 3’ end RNY5 cleavage is structure dependent. In high throughput mutagenesis experiments, cleavage occurred between the 2nd and 3rd nt above a double stranded stem comprising high GC content. We demonstrate that an internal loop above stem S3 is critical for producing 3’ end ysRNAs (31 nt) with mutants resulting in longer or no ysRNAs. We show a UGGGU sequence motif at position 22 of RNY5 is critical for producing 5’ end ysRNAs (22–25 nt). We show that intact RO60 is critical for ysRNA biogenesis. We conclude that ribonuclease L (RNASEL) contributes to Y RNA cleavage in mouse embryonic fibroblasts but is not the only endoribonuclease important in human cells.

Comparative genomics and selection analysis of Yeonsan Ogye black chicken with whole-genome sequencing.

Yeonsan Ogye (OGYE; Gallus gallus domesticus) is a rare indigenous chicken breed that inhabits the Korean Peninsula. This breed has completely black coloring, including plumage, skin, eyes, beak, and internal organs. Despite these unique morphological characteristics, the population of OGYE has declined without in-depth research into their genome research. Therefore, this study aimed to compare the whole genome of OGYE to 12 other chicken populations, including ancestral breed, commercial breeds, Chinese indigenous breeds, and Korean native chickens. We focused on revealing the selection signature of OGYE, which has occurred through environmental pressures in the Korean Peninsula. Genome-wide selection analysis has identified local adaptation traits, such as egg development, that contribute to fetal viability and innate immune response to prevent viral and microbes infection in OGYE. In particular, SPP1 (Secreted Phosphoprotein 1), HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1), and P2RX4 (Purinergic Receptor P2X 4) could have considerable involvement in egg development and RNASEL (Ribonuclease L), BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1), and TLR4 (Toll-Like Receptor 4) are crucial for the determination of the innate immune response. This study revealed the unique genetic diversity of OGYE at the genome-wide level. Furthermore, we emphasized the sustainable management of genetic resources and formulated breeding strategies for livestock on the Korean Peninsula.

A specific promoter-type in ribonuclease L gene is associated with phagocytic activity in pigs.

We have previously generated Large White pigs with high immune competence using a selection strategy based on phagocytic activity (PA), capacity of alternative complement pathway, and antibody response after vaccination against swine erysipelas. In this study, to identify the genetic changes caused by the immune selection pressure, we compared gene expression and polymorphisms in the promoter region between pigs subjected to the immune selection (immune-selected pigs) and those that were not (non-selected pigs). After lipid A stimulation, using a microarray analysis, 37 genes related to immune function and transcription factor activity showed a greater than three-fold difference in expression between macrophages derived from immune-selected and non-selected pigs. We further performed a polymorphic analysis of the promoter region of the differentially expressed genes, and elucidated the predominant promoter-types in the immune-selected and non-selected pigs, respectively, in the genes encoding ribonuclease L (RNASEL), sterile α motif and histidine-aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1, signal transducer and activator of transcription 3, and tripartite motif containing 21. Analysis of the association between these promoter genotypes and the immune phenotypes revealed that the immune-selected promoter-type in RNASEL was associated with increased PA and was inherited recessively. Considering that RNASEL has been reported to be involved in antimicrobial immune response of mice, it may be possible to enhance the PA of macrophages and improve disease resistance in pig populations using RNASEL promoter-type as a DNA marker for selection.

Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency.

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.

The Viral Defense Gene RNaseL Acts as a Regeneration Repressor

Mammalian injury responses are characterized by fibrosis and scarring rather than functional regeneration. Limited regenerative capacity in mammals could reflect a loss of pro-regeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we performed comprehensive transcript screening in human subjects after laser rejuvenation treatment. We searched for overlapping transcripts also associated with Wound Induced Hair Neogenesis (WIHN), a rare example of regeneration in mice. We found the anti-viral endoribonuclease RNase L to be a powerful suppressor of regeneration. Rnasel-/- mice exhibit remarkable regenerative capacity and accelerated wound healing following injury, through the production of IL-36α. Consistent with the known role of RNase L to stimulate caspase-1 signaling, we find that pharmacologic inhibition of caspases promotes regeneration in a novel IL-36-dependent manner. We also find a gene set of inner root sheath keratins, such as KRT71, that is associated with poor wound healing in mouse and man, and decreases with caspase inhibition. Finally, these responses are not limited to skin, but occur following intestinal injury as well, suggesting that suppression of regeneration is a general characteristic of epithelial wound healing. In all, this work suggests that RNaseL functions as a regeneration repressor gene in a functional tradeoff that prioritizes host antiviral abilities and is a target to enhance healing in multiple epithelial organs, perhaps even during viral infection.

Identification of Ankyrin Repeat, RNASE Domain of RNASE L Gene Mutation in Hepatocellular Carcinoma and its Association with HCV Viral Load

Background: Hepatocellular Carcinoma (HCC) is the most common primary malignant tumour of the liver. This is multiple risk factors are associated with its pathogenesis. Chronic liver infection via Hepatitis is by far most common cause of HCC worldwide. It is a viral infection by Hepatitis C virus (HCV), Hepatitis B virus (HBV) and Hepatitis D virus (HD). Pathogenesis of HCC is a combination of multiple genetic factors. Certain gene mutations are directly involved in the development of carcinoma; one that stands out most is RNASE-L. We assume that mutation of this gene also co-relates with viral load of hepatitis which in turn increases the severity of HCC. Methodology: This study was conducted in Dow University of Health Sciences, department of Molecular Pathology DDRRL and National Institute of Liver & GI Diseases (NILGID), we investigated 80 whole blood samples, from which we extracted DNA and then PCR performed. The amplified PCR products were sent to Macrogen, Korea for analysis and sequencing of RNASE-L gene mutation followed by sequence analysis via BioEdit and MEGA 7 software. After which HCV viral load was correlated with those sequences. Result: The categories of our sample were; 1) HCV positive patients, 2) HCV positive patients with HCC and 3) HCC diagnosed patients. Out of the 80 blood samples, 5% are of HCC, 50% are of HCC along with HCV, and the remaining blood samples are of HCV positive individuals. Out of which 57.5% are males and 42.5% are females. Sequence analysis revealed, only one sample to have SNV G>an in RNASE domain, and none of the samples have SNV in ARD. Conclusion: In this study we tried analyse the genetic aspect of HCC, so that it can help us therapeutically. Our health care system is in dire need of some immediate reforms that are necessary to control the prevalence of HCC.

Evidence from 40 Studies that 2 Common Single-Nucleotide Polymorphisms (SNPs) of RNASEL Gene Affect Prostate Cancer Susceptibility: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-Compliant Meta-Analysis.

BackgroundNumerous studies have evaluated the relationship between RNASEL gene polymorphisms (rs486907 G>A and rs627928 T>G) and the risk of cancer. However, many of the results have been controversial. To explore the role of RNASEL gene polymorphisms in prostate cancer, we carried out the present meta-analysis.Material/MethodsThe qualified articles were collected from PubMed, Web of Science, Scopus, CNKI, and WanFang databases to August 2018. A total 23 articles with 40 studies were incorporated into our analysis.ResultsOur data show that rs486907 was not associated with the risk of prostate cancer in any populations. Nevertheless, rs627928 was reported to promote the development of prostate cancer (T vs. G: OR=1.08, 95% CI=1.01–1.15; TT+TG vs. GG: OR=1.14, 95% CI=1.03–1.25) in allele and recessive models in overall populations. Stratified analyses showed that similar results were obtained in white populations.ConclusionsWe report the effect of rs627928 on the development of prostate cancer and confirm that rs486907 is not involved in the risk of prostate cancer in the current meta-analysis. However, research in larger populations is needed to validate our conclusions.

RNASEL 1623A>C variant is associated with the risk of prostate cancer in African descendants.

Association between ribonuclease L (RNASEL) gene 1623A>C polymorphism and prostate cancer (PCa) susceptibility has been assessed in large quantities of studies but with controversial conclusions. We undertook a pooled analysis containing 7397 PCa cases and 6088 control subjects to assess the correlation between RNASEL 1623A>C polymorphism and PCa risk. Moreover, we used enzyme-linked immunosorbent assay to test the serum RNASEL expression among patients enrolled in our centers and in-silico tools were also utilized. The overall results of our analysis indicated a positive relationship between 1623A>C variant and PCa risk (allelic contrast, odds ratio [OR] = 1.07; 95% confidence interval [CI] = 1.02-1.12; Pheterogeneity = 0.575; CC vs AA, OR = 1.14; 95% CI = 1.03-1.26; Pheterogeneity = 0.217; CC + CA vs AA, OR = 1.10; 95% CI = 1.01-1.19; Pheterogeneity = 0.303; and CC vs CA + AA, OR = 1.08; 95% CI = 1.00-1.17; Pheterogeneity = 0.298). In ethnicity subgroup analysis, similar results were especially indicated in African descendants. In addition, serum RNASEL levels in PCa cases with CC + CA genotypes were higher than those with AA genotypes. Our present study showed evidence that RNASEL 1623A>C polymorphism is related to PCa risk, especially in African descendants.

The RNASEL -1385G/A polymorphism is associated with risk of prostate cancer in Africans.

The RNASEL –1385G/A (rs486907) variant has been reported to be associated with increased risk of prostate cancer. However, these associations are not consistent among studies. To address this issue, we performed a meta-analysis to evaluate the association between RNASEL –1385G/A polymorphism and prostate cancer risk. The PubMed, Embase, and Web of Science databases were searched for relevant papers published in the past 20 years from 1997 to 2017. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of associations. Based on our search for manuscripts reporting prostate cancer susceptibility related to the rs486907 polymorphism, 16 case–control studies from 13 different publications were retrieved. No significantly positive associations were found for the polymorphism and prostate cancer susceptibility in the total population. When stratified by ethnicity, the results demonstrated that the –1385G/A polymorphism was associated with a decreased cancer risk in Africans (GG vs AA: OR =0.371, 95% CI =0.176–0.783; GG/GA vs AA: OR =0.368, 95% CI =0.175–0.776). We also found that the rs486907 polymorphism was associated with a decreased cancer risk in hospital-based controls (GG vs AA: OR =0.697, 95% CI =0.488–0.996; GG + GA vs AA: OR =0.701, 95% CI =0.502–0.978). Our meta-analysis suggests that polymorphism in the RNASEL gene is a protective factor against prostate cancer in Africans. Further studies using larger sample sizes should be conducted to elucidate the role of gene polymorphism in prostate cancer risk.

562P - Higher expression of Micro-RNA and Wnt signaling cascade in RNASEL candidate gene in prostate cancer

Background: Cancer is a heterogeneous disease with worldwide distribution and aberrant alterations in gene expression. Prostate cancer is the result of considerable mutation in genome that are expressed in epithelial cells of prostate gland. Methods: Current study guide us to identify the tools for detection of mutational signature in prostate gland and identified gene expression patterns was directed for targeted medical therapy and exploring the role of micro RNA and Wnt signaling cascade. Quantitative real time PCR was performed to determine the gene expression level. Results: Expression level of micro-RNA and Wnt signaling cascade in up regulation of RANSEL gene in prostate cancer was determined as well as FOXO is playing a key role. Results showed that the relative Mir 140, Mir 145 and Micro 328 genes expression level is significantly higher in prostate cancer patients which down regulate the FOXO 1 and FOXO 3 gene while as, TP53 expression is highly expressed in prostate cancer patients. The data was analyzed statistically by using ANOVA and DMR. Conclusions: We concluded that Mir 140, Mir 145, Micro 328, FOXO 1, FOXO 3 and TP 53 genes expression level and Wnt signaling cascade play an important role in up regulation of RNASEL gene in prostate cancer. Legal entity responsible for the study: Ethical review Committee, Punjab Medical College, Faisalabad. Funding: None Disclosure: All authors have declared no conflicts of interest.

Association of a common genetic variant in RNASEL and prostate cancer susceptibility.

The RNASEL gene (2’, 5’-oligoisoadenylate synthetase-dependent) encodes a ribonuclease that plays a significant role in the apoptotic and antiviral activities of interferons. Various studies have used polymorphisms in the RNASEL gene to evaluate prostate cancer risk but studies that show an association between RNASEL Arg462Gln (1385G>A, R462Q, rs486907) polymorphism and prostate cancer risk are somewhat inconclusive. To assess the impact of RNASEL Arg462Gln polymorphism on prostate cancer risk, we conducted a meta-analysis of all available studies including 11,522 patients and 10,976 control subjects. The overall results indicated no positive association between the variant and prostate cancer risk. However, in a subgroup analysis by ethnicity, obvious associations were observed in Hispanic Caucasians for allelic contrast (OR = 1.18, 95% CI = 1.00 - 1.39, Pheterogeneity = 0.010), homozygote comparison (OR = 1.50, 95% CI = 1.02 – 2.20, Pheterogeneity = 0.001), and the recessive genetic model (OR = 1.44, 95% CI = 1.01 - 2.05, Pheterogeneity = 0.002) ; and in African descendants for homozygote comparison (OR = 2.59, 95% CI = 1.29 – 5.19, Pheterogeneity = 0.194) and the recessive genetic model (OR = 2.61, 95% CI = 1.30 – 5.23, Pheterogeneity = 0.195). In conclusion, the RNASEL Arg462Gln polymorphism may contribute to the risk of developing prostate cancer in African descendants and Hispanic Caucasians. Further larger and well-designed studies are warranted to evaluate this association in detail.

The association between RNASEL R462Q polymorphism and prostate cancer.

The association between RNASEL R462Q polymorphism and prostate cancer.

Sex-specific effect of RNASEL rs486907 and miR-146a rs2910164 polymorphisms' interaction as a susceptibility factor for melanoma skin cancer.

The genetics of melanoma is complex and, in addition to environmental influences, numerous genes are involved or contribute toward melanoma predisposition. In this study, we evaluated the possible interaction between miR-146a and one of its putative targets ribonuclease L (RNASEL) in the risk of sporadic melanoma. Polymorphisms rs2910164 in miR-146a and rs486907 in the RNASEL gene have both independently been associated with the risk of different cancers, and an interaction between them has been observed in nonmelanoma skin cancer. Polymorphisms rs2910164 G/C and rs486907 A/G were genotyped by restriction fragment length polymorphism analysis in 304 sporadic melanoma patients and 314 control individuals. Genotype distribution between cases and controls for each of the two polymorphisms was compared using Fisher's exact test. Epistasis between the two polymorphisms was tested by a logistic regression model. In the present study, we observed a sex-specific effect of the miR-146a rs2910164 C allele restricted to individuals carrying the RNASEL rs486907 A allele as well. Men carrying this allelic combination have the highest risk of melanoma, whereas it seems to have no effect or even an opposite relationship to melanoma risk in the female population. The results reported in the present study suggest a sex-specific interaction between miR-146a and RNASEL genes in melanoma skin cancer susceptibility, and could account for possible discordant results in association studies when stratification according to sex is not performed.