Profile of common prostate cancer risk variants in an unscreened Romanian population

To find sequence variants affecting prostate cancer (PCA) susceptibility in an unscreened Romanian population we use a genome‐wide association study (GWAS). The study population included 990 unrelated pathologically confirmed PCA cases and 1034 male controls. DNA was genotyped using Illumina SNP arrays, and 24.295.558 variants were imputed using the 1000 Genomes data set. An association test was performed between the imputed markers and PCA. A systematic literature review for variants associated with PCA risk identified 115 unique variants that were tested in the Romanian sample set. Thirty of the previously reported SNPs replicated (P‐value < 0.05), with the strongest associations observed at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The replicated variants showing the most significant association in Romania are rs1016343 at 8q24.21 (P = 2.2 × 10^?4), rs7929962 at 11q13.3 (P = 2.7 × 10^?4) and rs9364554 at 6q25.2 (P = 4.7 × 10^?4). None of the variants tested in the Romanian GWAS reached genome‐wide significance (P‐value <5 × 10^?8) but 807 markers had P‐values <1 × 10^?4. Here, we report the results of the first GWAS of PCA performed in a Romanian population. Our study provides evidence that a substantial fraction of previously validated PCA variants associate with risk in this unscreened Romanian population.     

Association of caspase 8 promoter variants and haplotypes with the risk of breast cancer and its molecular profile in an Iranian population: A case-control study

Caspase 8 (CASP8) gene plays a key role in the regulation of apoptotic cell death. Expression variation in this gene has been associated with the risk of breast cancer. The aim of this study was to investigate the association of rs3834129 and rs3769821, as functional variants, and their haplotypes with molecular profile as well as the risk of breast cancer in an Iranian population. A case-control study was conducted on 812 participants including 293 breast cancer patients and 519 healthy controls. Genotyping was performed by polymerase chain reaction–based methods. Statistical analysis was performed using SPSS Ver16. The association between polymorphisms and haplotypes with the risk of breast cancer was estimated by calculating odds ratios (OR) and chi-square (χ²) tests. In comparison with ins allele (I) of rs3834129, carriers of del allele (D) showed a lower risk of breast cancer (OR, 0.65; 95% confidence interval [CI], 0.49-0.87; P = 0.004). The multivariate logistic regression model indicated DD genotype as an independent factor for a decreased risk of breast cancer in our population (OR, 0.18; 95% CI, 0.06-0.58; P = 0.004). Also, the C allele of rs3769821 was associated with a 43% increased risk of breast cancer (P = 0.005); however, after adjustment for confounding factors, no association with rs3769821 and breast cancer was observed. In addition, D-T haplotype and diplotype presented protective effects (P < 0.05). Our results indicate that genetic variations in the promoter region of CASP8 gene, especially rs3834129, may serve as a genetic risk factor for breast cancer in an Iranian population.     

Association between XPG polymorphisms and stomach cancer susceptibility in a Chinese population

Xeroderma pigmentosum group G (XPG) protein plays an important role in the DNA repair process by cutting the damaged DNA at the 3′ terminus. Previous studies have indicated some polymorphisms in the XPG gene are associated with stomach cancer susceptibility. We performed this hospital‐based case–control study to evaluate the association of four potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C and rs873601G>A) with stomach cancer susceptibility. The four single nucleotide polymorphisms (SNPs) were genotyped in 692 stomach cancer cases and 771 healthy controls. Logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association of interest. Of the studied SNPs, XPG rs873601G>A polymorphism was found to significantly associate with stomach cancer susceptibility (AA versus GG/AG: OR = 1.31, 95% CI = 1.03–1.66, P = 0.027). Combined analysis of all SNPs revealed that the individuals with two of risk genotypes had a significantly increased stomach cancer risk (OR = 1.52, 95% CI = 1.13–2.06). In the stratification analysis, the association between the rs873601AA genotype and stomach cancer risk was observed in older group (>59 year), as well as patients with non‐cardia stomach cancer. Further combined analysis indicated men, smokers, or non‐drinkers more than one risk genotypes had a significantly increased stomach cancer risk. Our results indicate that XPG rs873601G>A polymorphism may be associated with the risk of stomach cancer. Further prospective studies with different ethnicities and large sample sizes are needed to validate our findings.     

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

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

Association of chromosome 8q24 variants with prostate cancer risk in the Siberian region of Russia and meta-analysis

Compelling evidence demonstrates chromosome 8q24 as a prostate cancer susceptibility locus. In present work we studied whether the common variants of 8q24 region, rs6983267 and rs1447295, were associated with the sporadic prostate cancer risk in the Russian population. Polymorphisms were genotyped in 393 case and 384 control Russian Caucasian men from Siberia region. The A allele of rs1447295 was significantly associated with the risk of prostate cancer (OR[CI 95%] = 1.74 [1.26-2.4], p = 7.8 x 10(-4)). A common G-A haplotype for rs6983267 - rs1447295 also showed an association with prostate cancer risk in Russian population (OR[CI 95%] = 2.03 [1.1 - 3.75], p = 0.02). We performed a meta-analysis combining our results with previous studies to evaluate the association between studied SNPs and prostate cancer risk. Meta-analysis has strongly supported the association for these SNPs (p < 10(-6)). Accordingly our study confirms the association between chromosome 8q24 and prostate cancer risk.     

Association of chromosome 8q24 variants with prostate cancer risk in the Siberian region of Russia and meta-analysis

Compelling evidence demonstrates the importance of chromosome 8q24 as a locus of susceptibility to prostate cancer. In this work, the association of common 8q24 variants, rs6983267 and rs1447295, with a sporadic risk of prostate cancer was analyzed in the Russian population of Siberia. For this purpose, the above polymorphisms were genotyped in 393 cases and 384 control individuals. The A allele of rs1447295 was significantly associated with prostate cancer risk (OR[CI 95%] = 1.74 [1.26–2.4], p = 7.8 × 10⁻⁴). The common G-A haplotype of rs6983267-rs1447295 also showed association with prostate cancer risk in Russians (OR[CI 95%] = 2.03 [1.1–3.75], p = 0.02). A meta-analysis combining our data with previously published results was performed to better evaluate the association between the SNPs studied and prostate cancer risk; its results strongly supported the association for both loci (p < 10⁻⁶). Thus, our study has confirmed the association of chromosome 8q24 with a risk of prostate cancer.     

Association between common genetic variants in pre-microRNAs and gastric cancer risk in Japanese population

Background: Common single‐nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human cancers. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre‐miRNAs (miR‐196a2, miR‐146a, and miR‐499) with the risk of gastric cancer (GC) and peptic ulcer diseases, and with the severity of Helicobacter pylori‐induced gastritis in Japanese population. Methods: The rs11614913 (C>T), rs2910164 (G>C), and rs3746444 (A>G) SNPs were genotyped in 552 GC, and 697 non‐cancer subjects, including 141 gastric and 73 duodenal ulcer, and 483 non‐ulcer subjects. The degree of histologic gastritis was classified according to the updated Sydney System, and the serum pepsinogen levels were measured in selected 579 and 204 cases. Results: The rs2910164 CC genotype held a significantly higher risk of GC when compared to non‐cancer subjects (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.02–1.66, p =.03). Similarly, the rs2910164 C carrier was associated with higher risk of GC when compared to both non‐cancer and non‐ulcer subjects (OR = 1.39, 95%CI = 1.00–1.93, p =.05, adjusted OR = 1.57, 95%CI = 1.09–2.27, p =.016, respectively). The rs2910164 CC genotype was associated with non‐cardia and upper third, diffuse type and advanced stage GC. The rs11614913 TT genotype was associated with higher degree of mononuclear cell infiltration (score 0–1 vs 2～, adjusted OR = 1.62, 95%CI = 1.05–2.49, p =.03). Conclusions: The rs2910164 (G>C) SNP in the miR‐146a is associated with susceptibility to GC. In addition, the rs11614913 (C>T) SNP in the miR‐196a2 is associated with the degree of H. pylori‐induced mononuclear cell infiltration.     

ZEB1‐mediated vasculogenic mimicry formation associates with epithelial–mesenchymal transition and cancer stem cell phenotypes in prostate cancer

The zinc finger E‐box‐binding homeobox 1 (ZEB1) induced the epithelial–mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid–Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1‐induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT‐related and CSC‐associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p‐Src⁵²⁷ level but not p‐Src⁴¹⁶ level, while ZEB1 knockdown also down‐regulated the level of p‐Src⁵²⁷ in PC3 and DU‐145 cells. PP2 treatment also significantly reduced the expression of VE‐cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression.     

DGCR8 is essential for tumor progression following PTEN loss in the prostate

In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten‐knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null‐induced expansion of the basal‐like, but not luminal, cellular compartment. Furthermore, while late‐stage Pten knockout tumors exhibit decreased senescence‐associated beta‐galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 blocked these changes resulting in levels similar to wild type. Sequencing of small RNAs in isolated epithelial cells uncovered numerous miRNA changes associated with PTEN loss. Consistent with a Pten–Dgcr8 association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for microRNAs in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following Pten loss.     

Toll‐like receptors in prostate infection and cancer between bench and bedside

Toll‐Like receptors (TLRs) are a family of evolutionary conserved transmembrane proteins that recognize highly conserved molecules in pathogens. TLR‐expressing cells represent the first line of defence sensing pathogen invasion, triggering innate immune responses and subsequently priming antigen‐specific adaptive immunity. In vitro and in vivo studies on experimental cancer models have shown both anti‐ and pro‐tumoural activity of different TLRs in prostate cancer, indicating these receptors as potential targets for cancer therapy. In this review, we highlight the intriguing duplicity of TLR stimulation by pathogens: their protective role in cases of acute infections, and conversely their negative role in favouring hyperplasia and/or cancer onset, in cases of chronic infections. This review focuses on the role of TLRs in the pathophysiology of prostate infection and cancer by exploring the biological bases of the strict relation between TLRs and prostate cancer. In particular, we highlight the debated question of how reliable mutations or deregulated expression of TLRs are as novel diagnostic or prognostic tools for prostate cancer. So far, the anticancer activity of numerous TLR ligands has been evaluated in clinical trials only in organs other than the prostate. Here we review recent clinical trials based on the most promising TLR agonists in oncology, envisaging a potential application also in prostate cancer therapy.     

Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95 %CI 1.02–13.84, P = 0.046) and 8.0 (95 %CI 2.20–29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28–1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.     

KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta‐analysis of 15,736 patients

The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta‐analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random‐effect or fixed‐effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240–1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570–0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286–1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275–1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.     

Long non-coding RNA POLR2E gene polymorphisms increased the risk of prostate cancer in a sample of the Iranian population

The current study aimed to examine the impact of POLR2E rs1046040 and rs3787016 polymorphisms on prostate cancer (PCa) risk in a sample of southeast Iranian population. The present case-control study was performed on 178 patients with PCa and 180 benign prostatic hyperplasia (BPH). Genotyping of the variants was done by mismatch PCR-RFLP. The findings showed that the rs3787016 C?>?T variant significantly increased the risk of PCa in codominant (OR?=?1.84, 95% CI?=?1.12-3.03, P?=?0.018, CT vs CC), dominant (OR?=?1.88, 95% CI?=?1.63-3.05, P?=?0.011, CT?+?TT vas CC) and allele (OR?=?1.77, 95% CI?=?1.52-2.72, P?=?0.010, T vs C) inheritance model. Regarding rs1046040 C?>?T polymorphism, the findings revealed that the CT genotype significantly increased the risk of PCa compared to the CC genotype (OR?=?1.60, 95% CI?=?1.03-2.49, P?=?0.043). Furthermore, rs3787016 CT/rs1046040?CC as well as rs3787016 CT/rs1046040 CT increased the risk of PCa compared to the CC/CC genotype (p?=?0.029 and p?=?0.014, respectively). Haplotype analysis proposed that rs3787016 T/rs1046040 C significantly increased the risk of PCa compared to C/C (p?=?0.037). No significant association was observed between POLR2E variants and clinicopathological characteristics of PCa patients. In conclusion, the findings propose that POLR2E variants may be a risk factor for susceptibility to PCa in a sample of Iranian population.     

CYP24 splicing variants are associated with different patterns of constitutive and calcitriol-inducible CYP24 activity in human prostate cancer cell lines

24-Hydroxylase (CYP24) activity modulates in vitro and in vivo calcitriol metabolism and biologic effects. We have investigated, in human PC3, DU145 and LNCaP prostate cancer cell lines, the relationship of CYP24 single nucleotide polymorphisms (SNPs) and splicing and the variable patterns of baseline and calcitriol-inducible CYP24 activity. DU145 cells exhibit baseline CYP24 activity that is further induced by calcitriol. Baseline and inducible CYP24 activity were barely detectable in LNCaP cells. In PC3, baseline CYP24 activity was undetectable but induced by calcitriol. A different pattern of SNPs was identified at positions 24, 46, 146 and 198 in the intron between exons 9 and 10 of CYP24 gene in each cancer cell line. DU145 displayed baseline CYP24 splicing between exon 9 and exon 11; splicing was only observed in calcitriol treated LNCaP cells. Untreated PC3 had a mixed picture (splicing and no splicing); only the spliced form was seen after calcitriol treatment. These results demonstrate that calcitriol treatment modulates CYP24 splicing, and suggests that differences in CYP24 splicing are associated with different patterns of CYP24 activity.     

Functional variants of the chitinase 3-like 1 gene are associated with clinicopathologic outcomes and progression of prostate cancer

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in advanced stages of several cancer types, including prostate cancer (PCa). Impacts of genetic variants of CHI3L1 on PCa development have not yet been investigated. The most common well-studied genetic variations are single-nucleotide polymorphisms (SNPs). Therefore, the objective of this study was to explore associations of CHI3L1 SNPs with both the susceptibility to PCa and its clinicopathological development. Three promoter SNPs, rs6691378 (−1371, G>A), rs10399805 (−247, G>A) and rs4950928 (−131, C>G), and one non-synonymous SNP, rs880633 (+2950, T>C), were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 701 PCa patients and 701 healthy controls. Results indicated that there were no significant associations of PCa susceptibility with these four CHI3L1 SNPs. However, among elderly PCa patients (aged >65 years), it was observed that polymorphic variants (GA + AA) of CHI3L1 rs6691378 and 10399805 were significantly linked to reduced risks of several clinicopathological characteristics, including a high Gleason grade, advanced pathologic T stage and tumour cell invasion. Moreover, analyses of The Cancer Genome Atlas database revealed that CHI3L1 expression levels were elevated in PCa tissues compared with normal tissues. Interestingly, higher CHI3L1 expression levels were found to be associated with longer progression-free survival rates in PCa patients. Our findings indicated that levels of CHI3L1 may influence the progression of PCa, and the rs6691378 and 10399805 SNP genetic variants of CHI3L1 are linked to the clinicopathological development of PCa within a Taiwanese population.