RNASEL

Gene Summary

Gene:RNASEL; ribonuclease L (2',5'-oligoisoadenylate synthetase-dependent)
Aliases: RNS4, PRCA1
Location:1q25
Summary:This gene encodes a component of the interferon-regulated 2-5A system that functions in the antiviral and antiproliferative roles of interferons. Mutations in this gene have been associated with predisposition to prostate cancer and this gene is a candidate for the hereditary prostate cancer 1 (HPC1) allele. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:2-5A-dependent ribonuclease
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • C-Reactive Protein
  • Endoribonucleases
  • Odds Ratio
  • Germ-Line Mutation
  • Mutation
  • Base Sequence
  • Neoplasm Proteins
  • Androgen Receptors
  • DNA Mutational Analysis
  • Heterozygote
  • Cancer Gene Expression Regulation
  • Polymerase Chain Reaction
  • Jews
  • Case-Control Studies
  • Inflammation
  • Genetic Variation
  • Genetic Linkage
  • Cohort Studies
  • Genetic Predisposition
  • African Americans
  • Prostate
  • Adenocarcinoma
  • DNA Sequence Analysis
  • Single Nucleotide Polymorphism
  • Prostate-Specific Antigen
  • Cancer DNA
  • European Continental Ancestry Group
  • Pedigree
  • Genotype
  • Alleles
  • Missense Mutation
  • Tumor Suppressor Proteins
  • Oligoribonucleotides
  • Apoptosis
  • Chromosome 1
  • Polymorphism
  • Molecular Sequence Data
  • Age of Onset
  • Haplotypes
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: RNASEL (cancer-related)

Wang L, Zhang M, Liu DX
Knock-down of ABCE1 gene induces G1/S arrest in human oral cancer cells.
Int J Clin Exp Pathol. 2014; 7(9):5495-504 [PubMed] Free Access to Full Article Related Publications
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.

Karyadi DM, Zhao S, He Q, et al.
Confirmation of genetic variants associated with lethal prostate cancer in a cohort of men from hereditary prostate cancer families.
Int J Cancer. 2015; 136(9):2166-71 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Farzan SF, Karagas MR, Christensen BC, et al.
RNASEL and MIR146A SNP-SNP interaction as a susceptibility factor for non-melanoma skin cancer.
PLoS One. 2014; 9(4):e93602 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

San Francisco IF, Rojas PA, Torres-Estay V, et al.
Association of RNASEL and 8q24 variants with the presence and aggressiveness of hereditary and sporadic prostate cancer in a Hispanic population.
J Cell Mol Med. 2014; 18(1):125-33 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Schoenfeld JD, Margalit DN, Kasperzyk JL, et al.
A single nucleotide polymorphism in inflammatory gene RNASEL predicts outcome after radiation therapy for localized prostate cancer.
Clin Cancer Res. 2013; 19(6):1612-9 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Lee TY, Ezelle HJ, Venkataraman T, et al.
Regulation of human RNase-L by the miR-29 family reveals a novel oncogenic role in chronic myelogenous leukemia.
J Interferon Cytokine Res. 2013; 33(1):34-42 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Reza MA, Fahimeh G, Reza MH
Evaluation of xenotropic murine leukemia virus and its R426Q polymorphism in patients with prostate cancer in Kerman, southeast of Iran.
Asian Pac J Cancer Prev. 2012; 13(8):3669-73 [PubMed] Related Publications
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.

Castro FA, Koshiol J, Hsing AW, et al.
Inflammatory gene variants and the risk of biliary tract cancers and stones: a population-based study in China.
BMC Cancer. 2012; 12:468 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Jin W, Wu DD, Zhang X, et al.
Positive selection on the gene RNASEL: correlation between patterns of evolution and function.
Mol Biol Evol. 2012; 29(10):3161-8 [PubMed] Related Publications
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.

Arredondo M, de Bethencourt F, Treviño A, et al.
Short communication: RNASEL alleles and susceptibility to infection by human retroviruses and hepatitis viruses.
AIDS Res Hum Retroviruses. 2012; 28(10):1259-61 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Alvarez-Cubero MJ, Entrala C, Fernandez-Rosado F, et al.
Predictive value in the analysis of RNASEL genotypes in relation to prostate cancer.
Prostate Cancer Prostatic Dis. 2012; 15(2):144-9 [PubMed] Related Publications
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.

Lin DW, FitzGerald LM, Fu R, et al.
Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality.
Cancer Epidemiol Biomarkers Prev. 2011; 20(9):1928-36 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Batman G, Oliver AW, Zehbe I, et al.
Lopinavir up-regulates expression of the antiviral protein ribonuclease L in human papillomavirus-positive cervical carcinoma cells.
Antivir Ther. 2011; 16(4):515-25 [PubMed] Related Publications
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.

Barbisan G, Contreras A, Pérez LO, et al.
The effect of TP53 codon 72 and RNASEL codon 462 polymorphisms on the development of cervical cancer in Argentine women.
Cancer Genet. 2011; 204(5):270-7 [PubMed] Related Publications
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.

Mandal S, Abebe F, Chaudhary J
2'-5' oligoadenylate synthetase 1 polymorphism is associated with prostate cancer.
Cancer. 2011; 117(24):5509-18 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
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.

Kral M, Rosinska V, Student V, et al.
Genetic determinants of prostate cancer: a review.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011; 155(1):3-9 [PubMed] Related Publications
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.

Fesinmeyer MD, Kwon EM, Fu R, et al.
Genetic variation in RNASEL and risk for prostate cancer in a population-based case-control study.
Prostate. 2011; 71(14):1538-47 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: Linkage studies have implicated chromosome 1q24 as a putative locus for hereditary prostate cancer. The RNASEL gene maps to 1q24 and has been associated with prostate cancer risk in multiple family-based linkage studies. The RNASEL gene product combats viral infection by degrading viral RNA and inducing apoptosis of infected cells. Few studies have evaluated the role of RNASEL variants in unselected or sporadic prostate cancer, or have considered the potential interaction between RNASEL variants and patient characteristics associated with past infection.
METHODS: Ten SNPs in the RNASEL gene were genotyped in 1,308 prostate cancer cases and 1,267 age-matched controls from prior population-based, case-control studies. The association between each SNP and haplotype with prostate cancer risk was calculated using logistic regression. Associations stratified by Gleason score were evaluated using polytomous regression. The likelihood ratio test was used to investigate effect modification.
RESULTS: Two RNASEL SNPs were associated with overall increases in prostate cancer risk (OR = 1.13 for each variant allele of rs12723593; OR = 1.88 for any variant allele of rs56250729). Risk estimates did not vary substantially by Gleason score, but there was effect modification for the variant allele of rs635261 by history of prostatitis (P = 0.02).
CONCLUSIONS: This study identified three RNASEL variants that are associated with risk for prostate cancer. Further research is required to confirm these results and to better understand the potential role RNASEL variants may play in the etiology of sporadic prostate cancer.

Zhang LF, Mi YY, Qin C, et al.
RNASEL -1385G/A polymorphism and cancer risk: a meta-analysis based on 21 case-control studies.
Mol Biol Rep. 2011; 38(8):5099-105 [PubMed] Related Publications
Polymorphisms in the endoribonuclease L (RNASEL) gene have been hypothesized to increase the incidence of cancer. The common sequence variation in RNASEL, -1385G/A (rs486907) has been involved in several types of cancer risk. However, results of the related published studies remained conflicting rather than conclusive. To clarify the role of RNASEL -1385G/A genotype in global cancer, we performed a meta-analysis of all the available published studies involving 8,732 cancer patients and 8,748 control subjects. The overall results indicated that there was no major influence of the variant on cancer risk. However, stratified analysis by ethnicity showed that the RNASEL -1385G/A polymorphism has an increased cancer risk in African descendents in the homozygote comparison (OR = 2.59, 95% CI = 1.27-5.27), although no association was found in the analysis stratified by cancer type (OR = 1.12, 95% CI = 0.94-1.35). This meta-analysis suggested that the RNASEL -1385G/A polymorphism is associated with cancer risk in African descendents. To draw more comprehensive conclusions, further prospective studies with larger numbers of participants worldwide are still required to examine associations between RNASEL -1385G/A polymorphism and cancer risk.

Schneider R, Slater EP, Sina M, et al.
German national case collection for familial pancreatic cancer (FaPaCa): ten years experience.
Fam Cancer. 2011; 10(2):323-30 [PubMed] Related Publications
Familial pancreatic cancer (FPC) is a rare hereditary tumor syndrome. The 10-years experience of the national case collection for familial pancreatic cancer of Germany (FaPaCa) is reported. Since 1999 FaPaCa has collected families with at least two first-degree relatives with confirmed pancreatic cancer (PC), who did not fulfill the criteria of other hereditary tumor syndromes. Histopathological verification of tumor diagnoses, and genetic counseling were prerequisites for enrollment of families in FaPaCa. 94 of 452 evaluated families fulfilled the criteria for partaking in FaPaCa. PC represented the sole tumor entity in 38 (40%) families. In 56 families additional tumor types occurred, including breast cancer (n = 28), colon cancer (n = 20) and lung cancer (n = 11). In 70 (74%) families the pattern of inheritance was consistent with an autosomal dominant trait. Compared to the preceding generation, a younger age of onset was observed in the offspring of PC patients (median: 57 vs. 69 years), indicating anticipation. Mutation analyses of BRCA2, PALB2, CDKN2a, RNASEL, STK11, NOD2, CHEK2 and PALLD, revealed deleterious causative germline mutations of BRCA2 and PALB2 in 2 of 70 (3%) and 2 of 41 (4.9%) German FPC families, respectively. Prospective PC screening with EUS, MRI and MRCP detected precancerous lesions (IPMN, multifocal PanIN2/3) or carcinoma in 5.5% (4 of 72) to 12.5% (9 of 72) of individuals at risk, depending on histological verification. Appropriate inclusion of families at high risk for PC in registries, such as FaPaCa, provides a unique and excellent tool to gain clinical and genetic knowledge of FPC. Focused research projects can be conducted most efficiently, when data of different FPC registries are combined.

Danielson BP, Ayala GE, Kimata JT
Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions.
J Infect Dis. 2010; 202(10):1470-7 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: There are questions regarding the prevalence of xenotropic murine leukemia virus-related virus (XMRV) in patients with prostate cancer and its association with the RNASEL R462Q polymorphism. We therefore investigated whether XMRV infection could be found in patients with prostate cancer from the southern United States, and we sought to verify the association with the R462Q.
METHODS: Prostate tissue specimens of 144 patients with prostate cancer from the southern United States were genotyped for R462Q by real time polymerase chain reaction allelic discrimination and were screened for XMRV proviral DNA by nested polymerase chain reaction specific for the env gene.
RESULTS: The R462Q polymorphism was found at an allelic frequency of 0.33. XMRV was detected in 32 (22%) of the 144 patients. Patients were significantly more likely to test positive for XMRV in both tumor and normal tissue rather than either alone (κ = 0.64). A positive result for XMRV was not significantly correlated with the R462Q polymorphism (P = .82) or clinical pathological parameters of prostate cancer, including Gleason score (P = .29).
CONCLUSIONS: XMRV is detectable in normal and tumor prostate tissue from patients with prostate cancer, independent of R462Q. The presence of XMRV in normal tissue suggests that infection may precede cancer onset.

Meyer MS, Penney KL, Stark JR, et al.
Genetic variation in RNASEL associated with prostate cancer risk and progression.
Carcinogenesis. 2010; 31(9):1597-603 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.

Agalliu I, Leanza SM, Smith L, et al.
Contribution of HPC1 (RNASEL) and HPCX variants to prostate cancer in a founder population.
Prostate. 2010; 70(15):1716-27 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: Prostate cancer is a genetically complex disease with locus and disease heterogeneity. The RNASEL gene and HPCX locus have been implicated in hereditary prostate cancer; however, their contributions to sporadic forms of this malignancy remain uncertain.
METHODS: Associations of prostate cancer with two variants in the RNASEL gene (a founder mutation, 471delAAAG, and a non-synonymous SNP, rs486907), and with five microsatellite markers in the HPCX locus, were examined in 979 cases and 1,251 controls of Ashkenazi Jewish descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models.
RESULTS: There was an inverse association between RNASEL rs486907 and prostate cancer in younger men (<65 years) and those with a first-degree relative with prostate cancer; men with AA genotype had ORs of 0.64 and 0.47 (both P < 0.05), respectively, in comparison to men with GG genotype. Within the HPCX region, there were positive associations for allele 135 of bG82i1.1 marker (OR = 1.77, P = 0.01) and allele 188 of DXS1205 (OR = 1.65, P = 0.02). In addition, allele 248 of marker D33 was inversely associated (OR = 0.65, P = 0.05) with Gleason score ≥7 tumors.
CONCLUSIONS: Results suggest that variants in RNASEL contribute to susceptibility to early onset and familial forms of prostate cancer, whereas HPCX variants are associated with prostate cancer risk and tumor aggressiveness. The observation that a mutation predicted to completely inactivate RNASEL protein was not associated with prostate cancer, but that a missense variant was associated, suggests that the effect is due to either partial inactivation of the protein, and/or acquisition of a new protein activity.

Silverman RH, Nguyen C, Weight CJ, Klein EA
The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome.
Nat Rev Urol. 2010; 7(7):392-402 [PubMed] Related Publications
Xenotropic murine leukemia virus-related virus (XMRV) is an authentic, newly recognized human retrovirus first identified in prostate cancer tissues from men with a deficiency in the innate immunity gene RNASEL. At present, studies have detected XMRV at widely different rates in prostate cancer cases (0-27%) and in patients with chronic fatigue syndrome (CFS; 0-67%). Indirect or direct modes of carcinogenesis by XMRV have been suggested depending on whether the virus was found in stroma or malignant epithelium. Viral replication in the prostate might be affected by androgens, which stimulate XMRV through a transcriptional enhancer site in viral DNA. By contrast, host restriction factors, such as APOBEC3 and tetherin, inhibit virus replication. Immune dysfunction mediated by XMRV has been suggested as a possible factor in CFS. Recent studies show that some existing antiretroviral drugs suppress XMRV infections and diagnostic assays are under development. Although other retroviruses of the same genus as XMRV (gammaretroviruses) cause cancer and neurological disease in animals, whether XMRV is a cause of either prostate cancer or CFS remains unknown. Emerging science surrounding XMRV is contributing to our knowledge of retroviral infections while focusing intense interest on two major human diseases.

Bhosle S, Suppiah S, Molinaro R, et al.
Evaluation of cellular determinants required for in vitro xenotropic murine leukemia virus-related virus entry into human prostate cancer and noncancerous cells.
J Virol. 2010; 84(13):6288-96 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The newly identified retrovirus-the xenotropic murine leukemia virus-related virus (XMRV)-has recently been shown to be strongly associated with familial prostate cancer in humans (A. Urisman et al., PLoS Pathog. 2:e25, 2006). While that study showed evidence of XMRV infection exclusively in the prostatic stromal fibroblasts, a recent study found XMRV protein antigens mainly in malignant prostate epithelial cells (R. Schlaberg et al., Proc. Natl. Acad. Sci. U. S. A. 106:16351-16356, 2009). To help elucidate the mechanisms behind XMRV infection, we show that prostatic fibroblast cells express Xpr1, a known receptor of XMRV, but its expression is absent in other cell lines of the prostate (i.e., epithelial and stromal smooth muscle cells). We also show that certain amino acid residues located within the predicted extracellular loop (ECL3 and ECL4) sequences of Xpr1 are required for efficient XMRV entry. Although we found strong evidence to support XMRV infection of prostatic fibroblast cell lines via Xpr1, we learned that XMRV was indeed capable of infecting cells that did not necessarily express Xpr1, such as those of the prostatic epithelial and smooth muscle origins. Further studies suggest that the expression of Xpr1 and certain genotypes of the RNASEL gene, which could restrict XMRV infection, may play important roles in defining XMRV tropisms in certain cell types. Collectively, our data reveal important cellular determinants required for XMRV entry into different human prostate cells in vitro, which may provide important insights into the possible role of XMRV as an etiologic agent in human prostate cancer.

Alberti C
Hereditary/familial versus sporadic prostate cancer: few indisputable genetic differences and many similar clinicopathological features.
Eur Rev Med Pharmacol Sci. 2010; 14(1):31-41 [PubMed] Related Publications
Genetic factors and their interactions with environmental conditions and internal microenvironment influence the prostate cancer (PC) development, so that gene expression couldn't strictly occur on the basis of reductionist determinisms of DNA causality but should also conform to multifactorial and stochastic events, moreover, considering the pre-RNA alternative splicing-mediated multi-protein assemblying mechanisms. Nevertheless, after age and ethnic background, the strongest epidemiological risk factor for PC is a positive family history. However, apart from RNaseL-, ElaC2-, MSR1-genes, there are not other identified high-risk genetic variants which might be considered responsible for hereditary PC, moreover suggesting that familial PC is a genetically heterogeneous disease, many gene loci rather than a specific major susceptibility gene predisposing to it. Gene-environment interactions play a crucial role in cancer development especially when low penetrance genes, such as in case of genetic polymorphisms, are the major players. Several epidemiological studies show, in some families, a possible, either syncronous or metachronous, association of other tumors (breast, brain, gastrointestinal tumors, lymphomas) with PC, thus suggesting a common genetic background. As far as the role of androgen metabolism and androgen receptor (AR)-related genes in the development of familial PC is concerned, a small number of either guanine-guanine-cytosine (< 16) or cytosine-adenine-guanine (< 18) repeats appears to increase the AR activity, resulting in a raising PC risk. Regarding the expression of both androgen and estrogen receptor-related genes in sporadic and hereditary PC, the immunohistochemistry findings show that the percentage of AR-positive cancer cells is higher in hereditary PC than in sporadic forms, whereas the mean number of estrogen-alpha-receptor-positive stromal cells is higher in sporadic PC rather than in that hereditary. As for 5-alpha-steroid-reductase-2 gene, the dinucleotide thymine-adenine repeated 18 times on the last exon, confers an increased PC predisposition, as it is mainly shown in African-American populations. Also VDR gene, that is a component of ligand (steroid)-dependent nuclear transcription factor superfamily, shows various polymorphisms which appear to be associated with PC risk. Except an earlier age of onset, no anatomo-clinical and tumor progression peculiarities between hereditary and sporadic PC have been generally identified. Indeed, tumor progression and metastasis, both in hereditary and sporadic PC, are mainly influenced by a variety of biochemical and immune-mediated tumor microenvironmental conditions rather than by the hereditary genetic factors, thus gene expression associated with invasive ability representing a newly acquired genetic variant rather than a selection of pre-existent gene abnormalities in PC cells. It's questionable whether genetic testing of unaffected men of hereditary PC families might be actually useful. Nevertheless a suitable counselling must be proposed. Family history and/or gene profiling-guided preventive strategies for men at high risk of familial PC, range from dietary to drug measures. Cancer chemopreventive approaches may include 5-alpha-reductase inhibitors, histone deacetylase inhibitors, antioxidans, non-steroidal anti-inflammatory drugs, cholesterol-lowering statins, vitamin D analogues.

Beuten J, Gelfond JA, Franke JL, et al.
Single and multivariate associations of MSR1, ELAC2, and RNASEL with prostate cancer in an ethnic diverse cohort of men.
Cancer Epidemiol Biomarkers Prev. 2010; 19(2):588-99 [PubMed] Related Publications
Three genes, namely, ELAC2 (HPC2 locus) on chromosome 17p11, 2'-5'-oligoisoadenlyate-synthetase-dependent ribonuclease L (RNASEL, HPC1 locus), and macrophage scavenger receptor 1 (MSR1) within a region of linkage on chromosome 8p, have been identified as hereditary tumor suppressor genes in prostate cancer. We genotyped 41 tagged single nucleotide polymorphisms (SNPs) covering the three genes in a case-control cohort, which included 1,436 Caucasians, 648 Hispanics, and 270 African Americans. SNPs within MSR1, ELAC2, and RNASEL were significantly associated with risk of prostate cancer albeit with differences among the three ethnic groups (P = 0.043-1.0 x 10(-5)). In Caucasians, variants within MSR1 and ELAC2 are most likely to confer prostate cancer risk, and rs11545302 (ELAC2) showed a main effect independent of other significant SNPs (P = 2.03 x 10(-5)). A major haplotype G-A-C-G-C-G combining five SNPs within MSR1 was further shown to increase prostate cancer risk significantly in this study group. Variants in RNASEL had the strongest effects on prostate cancer risk estimates in Hispanics and also showed an interaction effect of family history. In African Americans, single SNPs within MSR1 were significantly associated with prostate cancer risk. A major risk haplotype C-G-G-C-G of five SNPs within ELAC2 was found in this group. Combining high-risk genotypes of MSR1 and ELAC2 in Caucasians and of RNASEL and MSR1 in Hispanics showed synergistic effects and suggest that an interaction between both genes in each ethnicity is likely to confer prostate cancer risk. Our findings corroborate the involvement of ELAC2, MSR1, and RNASEL in the etiology of prostate cancer even in individuals without a family history.

Hohn O, Krause H, Barbarotto P, et al.
Lack of evidence for xenotropic murine leukemia virus-related virus(XMRV) in German prostate cancer patients.
Retrovirology. 2009; 6:92 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: A novel gammaretrovirus named xenotropic murine leukemia virus-related virus (XMRV) has been recently identified and found to have a prevalence of 40% in prostate tumor samples from American patients carrying a homozygous R462Q mutation in the RNaseL gene. This mutation impairs the function of the innate antiviral type I interferon pathway and is a known susceptibility factor for prostate cancer. Here, we attempt to measure the prevalence of XMRV in prostate cancer cases in Germany and determine whether an analogous association with the R462Q polymorphism exists.
RESULTS: 589 prostate tumor samples were genotyped by real-time PCR with regard to the RNaseL mutation. DNA and RNA samples from these patients were screened for the presence of XMRV-specific gag sequences using a highly sensitive nested PCR and RT-PCR approach. Furthermore, 146 sera samples from prostate tumor patients were tested for XMRV Gag and Env antibodies using a newly developed ELISA assay. In agreement with earlier data, 12.9% (76 samples) were shown to be of the QQ genotype. However, XMRV specific sequences were detected at neither the DNA nor the RNA level. Consistent with this result, none of the sera analyzed from prostate cancer patients contained XMRV-specific antibodies.
CONCLUSION: Our results indicate a much lower prevalence (or even complete absence) of XMRV in prostate tumor patients in Germany. One possible reason for this could be a geographically restricted incidence of XMRV infections.

Schlaberg R, Choe DJ, Brown KR, et al.
XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors.
Proc Natl Acad Sci U S A. 2009; 106(38):16351-6 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV), another gammaretrovirus. We analyzed 334 consecutive prostate resection specimens, using a quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike results previously reported. This finding increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide evidence for an association of XMRV with malignant cells and with more aggressive tumors.

Tsilidis KK, Helzlsouer KJ, Smith MW, et al.
Association of common polymorphisms in IL10, and in other genes related to inflammatory response and obesity with colorectal cancer.
Cancer Causes Control. 2009; 20(9):1739-51 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
OBJECTIVE AND METHODS: The association of 17 candidate single nucleotide polymorphisms (SNPs) in IL10 and other immune response genes (CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and genes related to obesity (PPARG, TCF7L2, ADIPOQ, LEP) with colorectal cancer was investigated. Haplotype tagging SNPs were chosen for IL10, CRP, and TLR4. Incident colorectal cancer cases (n = 208) and matched controls (n = 381) were identified between baseline in 1989 and 2003 among participants in the CLUE II cohort. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression.
RESULTS: Compared with the AA genotype at the candidate IL10-1082 locus (rs1800896), carrying one (OR, 0.79; 95% CI, 0.53-1.18) or two (OR, 0.58; 95% CI, 0.35-0.95) G alleles, a known higher producer of the anti-inflammatory cytokine IL-10, was associated with lower risk of colorectal cancer (p trend = 0.03). Statistically significant associations with colorectal cancer were observed for three tagSNPs in IL10 (rs1800890, rs3024496, rs3024498) and one common haplotype, but these associations were due to high linkage disequilibrium with IL10-1082. Two CRP haplotypes (global p = 0.04) and TLR4 tagSNPs (rs7873784, rs11536891), but not TLR4 haplotypes, were associated with colorectal cancer.
CONCLUSIONS: Our study suggests that polymorphisms in IL10, and also possibly in CRP and other genes related to immune response or obesity may be associated with colorectal cancer.

Breyer JP, McReynolds KM, Yaspan BL, et al.
Genetic variants and prostate cancer risk: candidate replication and exploration of viral restriction genes.
Cancer Epidemiol Biomarkers Prev. 2009; 18(7):2137-44 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The genetic variants underlying the strong heritable component of prostate cancer remain largely unknown. Genome-wide association studies of prostate cancer have yielded several variants that have significantly replicated across studies, predominantly in cases unselected for family history of prostate cancer. Additional candidate gene variants have also been proposed, many evaluated within familial prostate cancer study populations. Such variants hold great potential value for risk stratification, particularly for early-onset or aggressive prostate cancer, given the comorbidities associated with current therapies. Here, we investigate a Caucasian study population of 523 independent familial prostate cancer cases and 523 age-matched controls without a personal or family history of prostate cancer. We replicate identified associations at genome-wide association study loci 8q24, 11q13, and 2p15 (P = 2.9 x 10(-4) to P = 4.7 x 10(-5)), showing study population power. We also find evidence to support reported associations at candidate genes RNASEL, EZH2, and NKX3-1 (P = 0.031 to P = 0.0085). We further explore a set of candidate genes related to RNASEL and to its role in retroviral restriction, identifying nominal associations at XPR1 and RBM9. The effects at 8q24 seem more pronounced for those diagnosed at an early age, whereas at 2p15 and RNASEL the effects were more pronounced at a later age. However, these trends did not reach statistical significance. The effects at 2p15 were statistically significantly more pronounced for those diagnosed with aggressive disease.

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