We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989-2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07-2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00-2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18-1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27-1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia.

BACKGROUND: Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes.
METHODS: In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers.
RESULTS: RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p < 0.002). Taqman genotyping demonstrated that the allele frequency of RNASEL:p.Glu265* was similar in affected and unaffected Australian women, consistent with other populations.
CONCLUSION: Our study suggests that RNASEL:p.Glu265* may be a genetic modifier of risk for early-onset breast cancer predisposition in carriers of high-risk mutations. Much larger case-case and case-control studies are warranted to test the association observed in this report.

African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR≥0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score≥7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent.

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.

BACKGROUND: Thymic adenocarcinoma is an extremely rare subtype of thymic epithelial tumors. Due to its rarity, there is currently no sequencing approach for thymic adenocarcinoma.
METHODS: We performed whole exome and transcriptome sequencing on a case of thymic adenocarcinoma and performed subsequent validation using Sanger sequencing.
RESULTS: The case of thymic adenocarcinoma showed aggressive behaviors with systemic bone metastases. We identified a high incidence of genetic aberrations, which included somatic mutations in RNASEL, PEG10, TNFSF15, TP53, TGFB2, and FAT1. Copy number analysis revealed a complex chromosomal rearrangement of chromosome 8, which resulted in gene fusion between MCM4 and SNTB1 and dramatic amplification of MYC and NDRG1. Focal deletion was detected at human leukocyte antigen (HLA) class II alleles, which was previously observed in thymic epithelial tumors. We further investigated fusion transcripts using RNA-seq data and found an intergenic splicing event between the CTBS and GNG5 transcript. Finally, enrichment analysis using all the variants represented the immune system dysfunction in thymic adenocarcinoma.
CONCLUSION: Thymic adenocarcinoma shows highly malignant characteristics with alterations in several cancer-related genes.

BACKGROUND: We reported that some, but not all single nucleotide polymorphisms (SNPs) in select immune response genes are associated with prostate cancer, but not individually with the prevalence of intraprostatic inflammation in the Prostate Cancer Prevention Trial (PCPT) placebo arm. Here, we investigated whether these same SNPs are associated with risk of lower- and higher-grade prostate cancer in men randomized to finasteride, and with prevalence of intraprostatic inflammation among controls. Methods A total of 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 were genotyped in 625 white prostate cancer cases, and 532 white controls negative for cancer on an end-of-study biopsy nested in the PCPT finasteride arm. We used logistic regression to estimate log-additive odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history.
RESULTS: Minor alleles of rs2243250 (T) in IL4 (OR = 1.46, 95% CI 1.03-2.08, P-trend = 0.03), rs1800896 (G) in IL10 (OR = 0.77, 95% CI 0.61-0.96, P-trend = 0.02), rs2430561 (A) in IFNG (OR = 1.33, 95% CI 1.02-1.74; P-trend = 0.04), rs3747531 (C) in MSR1 (OR = 0.55, 95% CI 0.32-0.95; P-trend = 0.03), and possibly rs4073 (A) in IL8 (OR = 0.81, 95% CI 0.64-1.01, P-trend = 0.06) were associated with higher- (Gleason 7-10; N = 222), but not lower- (Gleason 2-6; N = 380) grade prostate cancer. In men with low PSA (<2 ng/mL), these higher-grade disease associations were attenuated and/or no longer significant, whereas associations with higher-grade disease were apparent for minor alleles of rs1800795 (C: OR = 0.70, 95% CI 0.51-0.94, P-trend = 0.02) and rs1800797 (A: OR = 0.72, 95% CI 0.53-0.98, P-trend = 0.04) in IL6. While some IL10 tagSNPs were associated with lower- and higher-grade prostate cancer, distributions of IL10 haplotypes did not differ, except possibly between higher-grade cases and controls among those with low PSA (P = 0.07). We did not observe an association between the studied SNPs and intraprostatic inflammation in the controls.
CONCLUSION: In the PCPT finasteride arm, variation in genes involved in the immune response, including possibly IL8 and IL10 as in the placebo arm, may be associated with prostate cancer, especially higher-grade disease, but not with intraprostatic inflammation. We cannot rule out PSA-associated detection bias or chance due to multiple testing.

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (

BACKGROUND: There is contradictory evidence of the effects that environmental factors-dietary habits (ingestion rates of red meat, soy products, fish, etc.) and work environment (exposure to metals, pesticides, several toxic products, etc.)-and KLK3, AR, RNASEL, MSR1, and ELAC2 expression patterns have on prostate cancer (PCa). In our study, we investigated the potential association between KLK3, AR, RNASEL, MSR1, and ELAC2 polymorphisms, expression patterns, exposure to environmental factors, and PCa in a Spanish cohort. Blood and fresh tissue samples were collected from 322 subjects with prostate-specific antigen (PSA)>4ng/ml to determine their genotypes (RNASEL, MSR1, and ELAC2) and assess messenger ribonucleic acid expression levels (by quantitative amplification testing).
MAIN FINDINGS: Among clinical parameters, a 63.6% of patients with CC variants in rs11545302 (ELAC2) had PSA>20ng/ml (P = 0.008), and rs486907 (RNASEL), with 52.8% of patients with CT variants with Gleason score>7. Regarding TNM stage, patients with GG variants, rs4792311 (ELAC2) generally had stage 1 tumors. Genetic expression analysis revealed RNASEL (P = 0.007) was underexpressed in PCa tissue, whereas KLK3 (P = 0.041) was overexpressed. As to environmental factors, the intake of dried fruits (P = 0.036) and practice of sports (P = 0.024) revealed an effect in PCa. Moreover, environmental factors were observed to affect gene expression patterns. Thus, RNASEL (P = 0.018) and ELAC2 (P = 0.023) were found to be underexpressed in patients who ate processed foods frequently; MSR1 (P = 0.024) and AR (P = 0.004) were underexpressed in patients who did not practice sports; and KLK3 (P = 0.039; P = 0.046) underexpressed in patients exposed to dust and toxic products.
CONCLUSIONS: This is the first study to analyze the correlation between RNASEL, MSR1, and ELAC2 genotypes and messenger ribonucleic acid expression in PCa. RNASEL and KLK3 show different expression patterns in normal vs. tumor tissue, which supports their reported relevance in human cancer. The results obtained confirm that RNASEL plays a crucial role in PCa. Environmental factors such as exercise, exposure to toxic agents, and intake of processed foods are associated with PCa.

BACKGROUND: We previously reported that both intraprostatic inflammation and SNPs in genes involved in the immune response are associated with prostate cancer risk and disease grade. In the present study, we evaluated the association between these SNPs and intraprostatic inflammation in men without a prostate cancer diagnosis.
METHODS: Included in this cross-sectional study were 205 white controls from a case-control study nested in the placebo arm of the Prostate Cancer Prevention Trial. We analyzed inflammation data from the review of H&E-stained prostate tissue sections from biopsies performed per protocol at the end of the trial irrespective of clinical indication, and data for 16 SNPs in key genes involved in the immune response (IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, TNFA; 7 tagSNPs in IL10). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between carrying at least one minor allele and having at least one biopsy core (of a mean of three reviewed) with inflammation.
RESULTS: None of the SNPs evaluated was statistically significantly associated with having at least one core with inflammation. However, possible inverse associations were present for carrying the minor allele of rs2069762 (G) in IL2 (OR = 0.51, 95%CI 0.25-1.02); carrying two copies of the minor allele of rs1800871 (T) of IL10 (OR = 0.29, 95%CI 0.08-1.00); and carrying the minor allele of rs486907 (A) in RNASEL (OR = 0.52, 95%CI 0.26-1.06). After creating a genetic risk score from the three SNPs possibly associated with inflammation, the odds of inflammation increased with increasing number of risk alleles (P-trend = 0.008).
CONCLUSION: While our findings do not generally support a cross-sectional link between individual SNPs in key genes involved in the immune response and intraprostatic inflammation in men without a prostate cancer diagnosis, they do suggest that some of these variants when in combination may be associated with intraprostatic inflammation in benign tissue.

RNase L is a regulated endoribonuclease that functions in the interferon antiviral response. Activation of RNase L by 2', 5'-oligoadenylates has been linked to apoptosis, autophagy and inflammation. Genetic studies have also suggested the possible involvement of the RNase L gene (RNASEL) on chromosome 1q25.3 in several types of cancer. Here we report that ablation of RNase L in human prostate cancer PC3 cells by CRISPR/Cas9 gene editing technology enhanced cell migration as determined both by transwell assays and scratch wound healing assays. In addition, RNase L knockdown by means of RNAi increased migration of PC3 and DU145 cells in response to either fibronectin or serum stimulation, as did homozygous disruption of the RNase L gene in mouse embryonic fibroblasts. Serum or fibronectin stimulation of focal adhesion kinase (FAK) autophosphorylation on tyrosine-397 was increased by either knockdown or ablation of RNase L. In contrast, a missense mutant RNase L (R667A) lacking catalytic activity failed to suppress cell migration in PC3 cells. However, a nuclease-inactive mutant mouse RNase L (W630A) was able to partially inhibit migration of mouse fibroblasts. Consistent with a role for the catalytic activity of RNase L, transfection of PC3 cells with the RNase L activator, 2', 5'-oligoadenylate, suppressed cell migration. RNase L knockdown in PC3 cells enhanced tumor growth and metastasis following implantation in the mouse prostate. Our results suggest that naturally occurring mutations in the RNase L gene might promote enhanced cell migration and metastasis.

The aim of this study was to analyze the use of 12 single-nucleotide polymorphisms in genes ELAC2, RNASEL and MSR1 as biomarkers for prostate cancer (PCa) detection and progression, as well as perform a genetic classification of high-risk patients. A cohort of 451 men (235 patients and 216 controls) was studied. We calculated means of regression analysis using clinical values (stage, prostate-specific antigen, Gleason score and progression) in patients and controls at the basal stage and after a follow-up of 72 months. Significantly different allele frequencies between patients and controls were observed for rs1904577 and rs918 (MSR1 gene) and for rs17552022 and rs5030739 (ELAC2). We found evidence of increased risk for PCa in rs486907 and rs2127565 in variants AA and CC, respectively. In addition, rs627928 (TT-GT), rs486907 (AG) and rs3747531 (CG-CC) were associated with low tumor aggressiveness. Some had a weak linkage, such as rs1904577 and rs2127565, rs4792311 and rs17552022, and rs1904577 and rs918. Our study provides the proof-of-principle that some of the genetic variants (such as rs486907, rs627928 and rs2127565) in genes RNASEL, MSR1 and ELAC2 can be used as predictors of aggressiveness and progression of PCa. In the future, clinical use of these biomarkers, in combination with current ones, could potentially reduce the rate of unnecessary biopsies and specific treatments.

A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I-Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3' and 5' UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males.

BACKGROUND: We previously found that inflammation in benign prostate tissue is associated with an increased odds of prostate cancer, especially higher-grade disease. Since part of this link may be due to genetics, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial.
METHODS: We genotyped 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and seven tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum <7; N = 674) and higher (7-10; N = 172) grade, and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history.
RESULTS: The minor allele (C) of rs3212227 in IL12(p40) was associated with an increased risk of total (log additive: OR = 1.30, 95%CI 1.10-1.53; P-trend = 0.0017) and lower-grade (OR = 1.36, 95%CI 1.15-1.62; P-trend = 0.0004) prostate cancer. The minor allele (A) of rs4073 in IL8 was possibly associated with a decreased risk of higher-grade (OR = 0.81, 95%CI 0.64-1.02; P-trend = 0.07), but not total disease. None of the other candidates was associated with risk. The minor alleles of IL10 tagSNPs rs1800890 (A; OR = 0.87, 95%CI: 0.75-0.99; P-trend = 0.04) and rs3021094 (C; OR = 1.31, 95%CI 1.03-1.66, P-trend = 0.03) were associated with risk; the latter also with lower- (P-trend = 0.04) and possibly higher- (P-trend = 0.06) grade disease. These patterns were similar among men with PSA <2 ng/ml at biopsy.
CONCLUSION: Variation in some immune response genes may be associated with prostate cancer risk. These associations were not fully explained by PSA-associated detection bias. Our findings generally support the role of inflammation in the etiology of prostate cancer.

Adult acute lymphoblastic leukemia (ALL) is characterized by a high frequency of abnormal karyotypes some of which are related to outcome. Single nucleotide polymorphism (SNP) array analysis provides a highly sensitive platform to detect large and small genomic aberrations. SNP array profiling data in adult ALL are limited and further systematic studies of this patient group are needed. We performed a population-based SNP array analysis of genomic aberrations and their influence on survival in 66 Lithuanian 18-65 year old ALL patients diagnosed between 2007 and 2013. Most aberrations were detected in chromosome arm 9p, chromosome arm 6q, chromosome arm 13q, and chromosome 17. The recurrently targeted copy number abnormalities involved several leukemia-related genes-CDKN2A/B, MLL, IKZF1, PAX5, RB1, TP53, and ETV6. We identified several new recurrent aberrations with possible new target genes: SMARCA4 in 19p13.2, RNASEL in 1q25.3, ARHGEF12 in 11q23.3, and LYL1 in 19p13.2. Aberrations in chromosome 13 and the RB1 gene as well as CDKN2A/B gene status were related to the outcome.

PURPOSE: This study aims to explore the clinical characteristics of ATP binding cassette E1 (ABCE1) in oral squamous cell carcinomas (OSCC) and its roles in the proliferation, invasiveness, migration and apoptosis of the human oral squamous cell carcinoma cells CAL-27.
METHODS: The expression of ABCE1 and its target protein-RNase L, were first studied in tumor tissues of OSCC and adjacent non-tumor tissues. Moreover, CAL-27cells were transfected by ABCE1-specific shRNA, then MTT assay, the transwell and scratch assay were used to study cell proliferation and migration activity; the apoptosis rate and cell cycle distribution were tested by flow cytometry. Western blot and RT-PCR assay were adopted to measure their silencing efficacy.
RESULTS: ABCE1 expression is low in the adjacent non-tumor tissues while the expression is high in the oral cancer; the expression is reversely proportional to the differentiation degrees. The expression of RNaseL was in contrary to ABCE1. After transfected with ABCE1-siRNA, the proliferation, invasiveness and migration capabilities of cells decreased significantly whilst the apoptosis rate enhanced greatly (P < 0.01). Meanwhile, the expression of ABCE1 in CAL-27 cells was blocked (P < 0.01) while the expression of RNase L increased significantly (P < 0.01).
CONCLUSION: ABCE1 is closely connected with the pathogenesis and development of oral cancer, which acts through the cellular pathways of 2-5A/RNase L.

Germline genetic variants have been suggested as prognostic biomarkers for identifying patients at high risk for lethal prostate cancer (PCa). Validation studies have confirmed the association of several single nucleotide polymorphisms (SNPs) with fatal PCa, but whether these variants affect PCa-specific mortality (PCSM) in patients with an inherited predisposition to PCa, based on familial history, is unknown. For this study, a cohort of 957 PCa patients from 270 hereditary prostate cancer families of European ancestry was genotyped for a panel of 22 PCSM-associated SNPs. Death certificates were reviewed to confirm cause of death. Mixed-effect Cox proportional hazards models were used to assess survival according to genotypes, accounting for relatedness and clinicopathological factors. Within this cohort, 98 PCa deaths were confirmed over an average follow-up period of 12.7 years after diagnosis. Variant allele carriers for three SNPs had significantly altered risk for PCSM [rs635261 at RNASEL, hazard ratio (HR), 0.35, 95% CI, 0.18-0.66; p = 0.002; rs915927 in XRCC1, HR, 1.91, 95% CI, 1.21-3.02; p = 0.009; and rs2494750 at AKT1, HR, 0.45, 95% CI, 0.23-0.90; p = 0.016). These results confirm the association of genetic variation in three genes with PCa lethality in a cohort of men with an inherited susceptibility to the disease and provide validation evidence that germline SNPs provide prognostic information for PCa patients. Development of a panel of germline biomarkers with clinical utility for distinguishing patients at detection who have an increased risk for fatal PCa is warranted.

Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (ORGC = 0.73, [95%CI = 0.52-1.03]; ORCC = 0.29, [95% CI = 0.14-0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (ORAG = 0.88, [95%CI = 0.65-1.19]; ORAA = 0.68, [95%CI = 0.43-1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (ORSCC = 0.56, [95%CI = 0.38-0.81], p-interaction = 0.012) and BCC (ORBCC = 0.57, [95%CI = 0.40-0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology.

To study the association between the polymorphisms Arg462Gln and Asp541Glu from the RNASEL gene (1q25), and the polymorphisms rs620861, rs1447295, rs6983267, rs7837328 from the chromosome 8q24 with the risk of presenting prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population. The study was performed on 21 control patients and 83 patients diagnosed with PCa. Polymorphisms were analysed from blood samples through real-time PCR by using TaqMan probes, and the genetic analysis was performed with the SNPStats program. Also, a comparison was performed between clinical characteristics of PCa and the presence of the different polymorphism genotypes by using the Minitab software. There was a significant association between the genotype G/G from the polymorphism rs6983267 with an overall increased risk of PCa, in patients both with or without family history of PCa (OR = 4.47, 95% CI = 1.05-18.94, P = 0.034 and OR = 3.57, 95% CI = 0.96-13.35, P = 0.037, respectively). Regarding clinical parameters, patients carrying the genotype C/C from the polymorphism Asp541Glu had significantly higher prostate-specific antigen (PSA) levels than patients carrying the other genotypes (P = 0.034). Moreover, patients with the genotype G/G of rs6983267 had higher PSA levels (P = 0.024). The polymorphism rs6983267 from region 3 of the chromosome 8q24 appears to be a prominent risk factor for PCa and a biomarker for cancer aggressiveness in the group of patients who presented higher levels of PSA at the time of diagnosis.

PURPOSE: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy.
EXPERIMENTAL DESIGN: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence.
RESULTS: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45-0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40-0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36-0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction = 0.02).
CONCLUSION: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management.

The endoribonuclease RNase-L is the terminal component of an interferon-regulated RNA decay pathway known as the 2'-5'-oligoadenylate (2-5A) system, whose established functions include antimicrobial and tumor suppressive activities. RNase-L activity requires binding of the small molecule 2-5A, leading to RNase-L dimerization and cleavage of single-stranded RNA. RNase-L expression is controlled post-transcriptionally by its 3'-untranslated region (3' UTR), which exerts a strong negative effect on RNase-L levels. MicroRNAs (miRNAs) are a class of small noncoding RNAs that repress expression of target genes by binding to regions of complementarity often in the 3' UTR. The miR-29 family acts as a tumor suppressor in several cancers, including acute and chronic myelogenous leukemia (CML), and has many oncogenic targets. We report that the miR-29 family represses RNase-L protein expression across several cell types. Using a luciferase reporter, we showed that miR-29 acts via 4 target sites within the RNASEL 3' UTR. Mutation of all sites is required for abrogation of miR-29 repression. In light of the reported tumor suppressive role of miR-29 in K562 CML cells and miR-29 repression of RNase-L in these cells, we generated K562 cells with stable RNase-L knockdown and demonstrated that loss of RNase-L inhibits proliferation in vitro as well as tumor growth in a xenograft model. Our findings identify a previously unknown miRNA regulator of RNase-L expression and support a novel oncogenic role for RNase-L in CML and potentially other hematopoietic malignancies.

A role for the xenotropic murine leukemia virus (XMRV) in prostate cancer development has been postulated. To answer questions regarding the prevalence of XMRV in Iranian patients with prostate cancer and its association with the RNASEL R462Q polymorphism, we here investigated a series of cases in Kerman, in the Southeast of Iran, and sought to verify the association with the R462Q using Real Time PCR Method. Prostate tissue specimens of 200 patients with prostate cancer were genotyped for R462Q by real time polymerase chain reaction allelic discrimination and were screened for XMRV proviral DNA by real time polymerase chain reaction specific for the envelope gene. Of 200 patients in this study 8 (4%) cases were positive for XMRV, the QQ allele being the most frequent regarding the R426Q polymorphism while in negative patients it was the RQ allele. There was significant correlation between high pathological scores and XMRV positive samples. No significant relationship was found between age groups and XMRV results. XMRV was only found in patients with QQ and RQ alleles, not RR. XMRV is detectable in tumor prostate tissue from some patients with prostate cancer, independent of R462Q.

BACKGROUND: Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.
METHODS: To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population-based case-control study in Shanghai, China.
RESULTS: Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).
CONCLUSION: These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.

RNASEL is a 2-5A-dependent endoribonuclease that is a component of the interferon-induced 2-5A system, which plays a crucial role in the antiviral and apoptotic activities of interferons. In humans, many polymorphic sites within the RNASEL gene have been associated with an increased risk of developing prostate cancer. Here, we obtained coding sequences for the RNASEL gene from 11 primates and found evidence that positive selection has operated on the C-terminal endoribonuclease domain and the N-terminal ankyrin repeats domain of the protein, domains that directly interact with virus (i.e., ankyrin repeats are responsible for receiving environmental signals, and the endoribonuclease catalyses the destruction of the pathogenic viral RNA). To extend this finding, we studied variation within this gene in modern human populations by resequencing alleles from 144 individuals representing four separate populations. Interestingly, the frequency of the 541D allele shows a negative association with the incidence rate of prostate cancer in worldwide populations, and haplotypes containing the 541D polymorphisms demonstrate signatures of positive selection. RNASEL variants having the 541D haplotype likely have a greater ability to defend against infections by viruses, thus the loss of this activity may be associated with the development of prostate cancer. We provide evidence that positive selection has operated on the RNASEL gene, and its evolution is correlated with its function in pathogen defense and cancer association.

RNASEL seems to function as an intracellular restriction factor blocking the establishment of infections caused by viral agents. Herein, we investigated whether allelic variants at the RNASEL gene might influence the susceptibility to viral infections or conditions potentially linked to viral agents. The allelic distribution at codon 462 was 139 (33.9%), 204 (49.8%), and 67 (16.3%) for RR, RQ, and QQ, respectively, in 410 individuals in Spain. There were no significant differences comparing 105 blood donors and 71 patients with HIV-1 infection, 27 with chronic hepatitis C, 67 with prostate cancer, and 107 with chronic fatigue syndrome. In contrast, two-thirds of 18 patients with HTLV-1 infection and 15 with chronic hepatitis B harbored RR. Thus, polymorphisms at the RNASEL gene do not seem to influence the susceptibility to common viral infections or conditions potentially of viral etiology. The role in influencing the susceptibility to HTLV-1 or HBV chronic infection warrants further examination in larger patient populations.

BACKGROUND: We would like to compare the different RNASEL genotypes with the stage of the cancer using parameters such as PSA levels, Gleason score and T-stage, and to develop a clinical protocol for the monitoring of the disease for trying a better evolution of the patient.
METHODS: A total of 231 patients with sporadic prostate cancer and 100 of controls were genotyped in RNASEL gene by sequencing the exons 1 and 3. A survey of clinical information was collected by a specialist following the Helsinki protocol. All patients and controls were interviewed by a researcher and signed their informed consent to participation in the study, which was approved by Ethics Committee of the hospital. The genetic information was processed and collected with an ABI PRISM Genetic Analyser 3130 using SeqScape software v.2.6. All the patients were analysed by comparing the genetic and clinical data. χ(2)-tests, Monte Carlo, Fisher tests and contigency tables were performed using SPSS v.15.0 and ARLEQUIN v.3.5 software on patient population.
RESULTS: Significant differences were found only between patients and controls in D541E, R461Q and I97L genotypes, the remainder of the variants did not seem relevant to our population in contrast to other populations, such as north-Caucasians, Afro Americans and Ashkenazi Jews. The genotypes associated with the worst prognoses are G/G in D541E, A/A in R462Q and A/G in I97L. The controls were included in our study to determine an approximation of the genotype in our population compared with the patients, but they did not account for the statistical process.
CONCLUSIONS: The genetic profile of patients with this cancer combined with other parameters could be used as a prognosis factor in deciding to give more radical and frequent treatments, depending on personal genotype.

BACKGROUND: Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer.
METHODS: In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P ≤ 0.01, FDR ≤ 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients.
RESULTS: Five SNPs were validated (P ≤ 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2-1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (P(trend) = 0.001), adjusting for clinicopathologic factors known to influence prognosis.
CONCLUSION: Five genetic markers were validated to be associated with lethal prostate cancer.
IMPACT: This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated.

BACKGROUND: We have previously shown that the HIV protease inhibitor lopinavir has selective toxicity against human papillomavirus (HPV)-positive cervical carcinoma cells via an unknown mechanism.
METHODS: SiHa cervical carcinoma cells were stably transfected with the proteasome sensor vector pZsProSensor-1 to confirm lopinavir inhibits the proteasome in these cells. The Panorama Xpress profiler 725 antibody array was then used to analyse specific changes in protein expression in lopinavir-treated versus control untreated SiHa cells followed by PCR and western blotting. Colorimetric growth assays of lopinavir-treated E6/E7 immortalised versus control human keratinocytes were performed. Targeted small interfering RNA gene silencing followed by growth assay comparison of lopinavir-treated/untreated SiHa cells was also used.
RESULTS: Lopinavir induced an increase in the fluorescence of pZsProSensor-1 transfected SiHa cells, indicative of proteasomal inhibition. Ribonuclease L (RNASEL) protein was shown to be up-regulated in lopinavir-treated SiHa cells, which was confirmed by PCR and western blot. Targeted silencing of RNASEL reduced the sensitivity of SiHa cells to lopinavir. Selective toxicity against E6/E7 immortalised keratinocytes versus control cells was also seen with lopinavir and was associated with up-regulated RNASEL expression.
CONCLUSIONS: These data are consistent with the toxicity of lopinavir against HPV-positive cervical carcinoma cells being related to its ability to block viral proteasome activation and induce an up-regulation of the antiviral protein RNASEL. This is supported by the drug's selective toxicity and up-regulation of RNASEL in E6/E7 immortalised keratinocytes combined with the increased resistance to lopinavir observed in SiHa cells following silencing of RNASEL gene expression.

Epidemiological evidence suggests that genetic factors, such as variants in cancer suppressor genes, may play an important role in the etiology of cervical carcinoma. TP53 is an outstanding cell cycle regulator, mutated in most human cancers, and RNASEL is thought to be involved in antiviral and apoptotic responses. To determine whether TP53 Arg72Pro and RNASEL Arg462Gln polymorphisms are associated with susceptibility to cervical cancer, a case-control study of 98 cancer patients and 123 healthy controls was conducted. Cervical samples were genotyped for both polymorphisms by pyrosequencing technology. The association between cervical cancer risk and the studied SNPs was evaluated by logistic regression, and potential gene-gene interactions were studied by Multifactor Dimensionality Reduction analysis. In the single-locus analysis, only the heterozygous TP53 Arg72Pro genotype was significantly associated with the risk of developing a cervical carcinoma, while the RNASEL polymorphism showed no association after age adjustment. In addition, the combination of both polymorphisms gives near-null information gain. Consequently, the effect provided by each single nucleotide polymorphism individually is considered higher than the effect resulting from the interaction between these two genes in cervical cancer risk. These results suggest that a heterozygous TP53 Arg72Pro genotype may contribute to cervical cancer susceptibility.

BACKGROUND: The antiviral, proapoptotic, antiproliferative gene 2'-5' oligoadenylate synthetase (2-5OAS1) converts adenosine triphosphate into a series of 2'-5' oligoadenylates (2-5A). In turn, 2-5A activates latent ribonuclease (RNaseL), a candidate hereditary prostate cancer gene. OAS1 polymorphism (reference single nucleotide polymorphism [SNP] 2660 [rs2660]) has been associated with increased susceptibility to infections and various diseases. In general, the low-enzyme-activity adenine-adenine (AA) genotype promotes susceptibility, whereas the high-enzyme-activity guanosine-guanosine (GG) genotype confers protection. In this study, the authors investigated the association of this functional OAS1 polymorphism (rs2660) with prostate cancer.
METHODS: Sample size and power were calculated using a power calculation software program for case-control genetic association analyses. Genomic DNA samples from a control group (n = 140) and from a case group of patients with prostate cancer (n = 164) were used for genotyping SNPs rs2660, rs1131454, and rs34137742 in all samples. Statistical analyses were performed using a logistic regression model.
RESULTS: A significant association was observed between the rs2660 genotype (A/G) and prostate cancer. Genotype AA increased the risk, whereas genotype GG decreased the risk of prostate cancer. The GG genotype was not observed in the African American samples. The AA genotype also increased the risk of prostate cancer with age.
CONCLUSIONS: The OAS1 SNP rs2660 AA genotype was associated significantly with prostate cancer, whereas the GG genotype protected against prostate cancer. OAS1 rs2660 may be a prostate cancer susceptibility polymorphism, which is a significant observation, especially in a context of the OAS1-RNaseL pathway. Thus, a functional defect in OAS1 because of the rs2660 SNP not only can attenuate RNaseL function but also can alter cell growth and apoptosis independent of RNaseL.

BACKGROUND: In prostate cancer, early detection and appropriate treatment remain key approaches. But given the constantly increasing incidence, prostate cancer ethiopathogenetic determinants are a current focus of attention. Although the development of this cancer is influenced by both environmental and genetic factors which are as yet ill-defined, genetic studies have revealed gene abnormalities which may be specifically associated with the risk of prostate cancer: changes in genes for the androgen receptor, RNAseL, ELAC2, MSR1, BRCA 1 and 2, HPCX, KLF6, HPC20 and fusion genes, e.g. TMPRSS2-ERG). Despite differing research results from molecular biological studies, these techniques can assist in earlier diagnosis enabling timely initiation of treatment.
METHODS: Methods and literature: MEDLINE search was performed to collect both original and review articles addressing prostate cancer and genetic risk factors using key words genetics, prostate cancer and risk.
CONCLUSIONS: A number of potential genetic risk factors/markers has been identified which may in near future contribute to earlier diagnosis of prostate cancer so that earlier treatment can be started. Despite many promising data we have found differing results and therefore we suppose further research should be conducted to achieve more precise conclusion. This review focuses on current knowledge of the genetic factors affecting the development of prostate cancer.