Association of rs6983267 at 8q24, HULC rs7763881 polymorphisms and serum lncRNAs CCAT2 and HULC with colorectal cancer in Egyptian patients.
ABSTRACT: The impact of HULC rs7763881 on colorectal cancer (CRC) susceptibility is not yet known. Also, the biological function of the cancer-related rs6983267 remains unclear. We investigated the association of these SNPs with the risk of CRC and adenomatous polyps (AP), their correlation with CCAT2 and HULC expression, and the potential of serum CCAT2 and HULC as biomarkers for CRC. 120 CRC patients, 30 AP patients, and 96 healthy controls were included. Genotyping and serum lncRNAs were assayed by qPCR. Studied SNPs were not associated with AP susceptibility. rs6983267 GG was associated with increased CRC risk, whereas rs7763881 AC was protective. rs7763881 and rs6983267 CT haplotype was protective. Serum CCAT2 and HULC were upregulated in CRC and AP patients versus controls and discriminated these groups by ROC analysis. rs6983267 GG and rs7763881 AA patients demonstrated higher serum CCAT2 and HULC compared with GT/TT and AC, respectively. rs6983267 and serum HULC predicted CRC diagnosis among non-CRC groups (AP?+?controls) by multivariate analysis. Studied SNPs or serum long noncoding RNAs weren't correlated with nodal or distant metastasis. In conclusion, rs6983267 and rs7763881 are potential genetic markers of CRC predisposition and correlate with serum CCAT2 and HULC, two novel potential non-invasive diagnostic biomarkers for CRC.
Project description:BACKGROUND: Recently, several studies have demonstrated that two long non-coding RNAs (lncRNAs), HULC and MALAT1, may participate in hepatocellular carcinoma (HCC) development and progression. However, genetic variations in the two lncRNAs and their associations with HCC susceptibility have not been reported. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in HULC and MALAT1 may contribute to HCC risk. METHODS: We conducted a case-control study and genotyped two SNPs, rs7763881 in HULC and rs619586 in MALAT1, in 1300 HBV positive HCC patients, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the associations between the two SNPs and susceptibility to HCC and HBV chronic infection. RESULTS: The variant genotypes of rs7763881 were significantly associated with decreased HCC risk in a dominant genetic model [AC/CC vs. AA: adjusted odds ration (OR) ?=? 0.81, 95% confidence intervals (CIs) ?=? 0.68-0.97, P ?=? 0.022]. Furthermore, the variant genotypes of rs619586 was associated with decreased HCC risk with a borderline significance (AG/GG vs. AA: adjusted OR ?=? 0.81, 95% CIs ?=? 0.65-1.01, P ?=? 0.057). However, no significant association was found between the two SNPs and HBV clearance. CONCLUSIONS: The variant genotypes of rs7763881 in HULC may contribute to decreased susceptibility to HCC in HBV persistent carriers.
Project description:Up-regulation of long non-coding RNAs (lncRNAs), colon-cancer associated transcript (CCAT) 1 and 2, was associated with worse prognosis in colorectal cancer (CRC). Nevertheless, their role in predicting metastasis in early-stage CRC is unclear. We measured the expression of CCAT1, CCAT2 and their oncotarget, c-Myc, in 150 matched mucosa-tumour samples of early-stage microsatellite-stable Chinese CRC patients with definitive metastasis status by multiplex real-time RT-PCR assay. Expression of CCAT1, CCAT2 and c-Myc were significantly up-regulated in the tumours compared to matched mucosa (p?<?0.0001). The expression of c-Myc in the tumours was significantly correlated to time to metastasis [hazard ratio?=?1.47 (1.10-1.97)] and the risk genotype (GG) of rs6983267, located within CCAT2. Expression of c-Myc and CCAT2 in the tumour were also significantly up-regulated in metastasis-positive compared to metastasis-negative patients (p?=?0.009 and p?=?0.04 respectively). Nevertheless, integrating the expression of CCAT1 and CCAT2 by the Random Forest classifier did not improve the predictive values of ColoMet19, the mRNA-based predictor for metastasis previously developed on the same series of tumours. The role of these two lncRNAs is probably mitigated via their oncotarget, c-Myc, which was not ranked high enough previously to be included in ColoMet19.
Project description:Previous studies have revealed that genetic variation in genes that regulate cell migration might be associated with susceptibility to recurrent spontaneous abortion. HULC regulates the migration of a variety of cells, and genetic polymorphisms of HULC are associated with susceptibility to a variety of diseases, but their association with susceptibility to recurrent spontaneous abortion has not been reported. This study included 610 cases of recurrent spontaneous abortion and 817 normal controls, and the polymorphisms of the four SNPs were genotyped using the TaqMan method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the associations between selected SNPs and susceptibility to recurrent spontaneous abortion. Our results showed that three SNPs were significantly associated with a reduced risk of recurrent spontaneous abortion: rs1041279 (GG vs. GC/CC: adjusted OR = 0.745, 95% CI = 0.559-0.993, P = 0.0445), rs7770772 (GC/CC vs. GG: adjusted OR = 0.757, 95% CI = 0.606-0.946, P = 0.0143), and rs17144343 (AA/GA vs GG adjusted OR = 0.526, 95% CI = 0.366-0.755, P = 0.0005). Individuals with one to four genotypes showed a reduced risk of recurrent spontaneous abortion (adjusted OR = 0.749, 95% CI = 0.598-0.939, P = 0.0123). This cumulative effect on protection increased with increases in the observed number of genotypes (adjusted OR = 0.727, 95% CI = 0.625-0.846, ptrend < 0.0001). Our study suggests that HULC might be a biomarker for risk for recurrent spontaneous abortion, but larger sample studies are needed to verify this result.
Project description:Red and processed meat have been associated with increased risk of colorectal cancer (CRC), whereas long-term use of non-steroid anti-inflammatory drugs (NSAIDs) may reduce the risk. The aim was to investigate potential interactions between meat intake, NSAID use, and gene variants in fatty acid metabolism and NSAID pathways in relation to the risk of CRC. A nested case-cohort study of 1038 CRC cases and 1857 randomly selected participants from the Danish prospective "Diet, Cancer and Health" study encompassing 57,053 persons was performed using the Cox proportional hazard model. Gene variants in SLC25A20, PRKAB1, LPCAT1, PLA2G4A, ALOX5, PTGER3, TP53, CCAT2, TCF7L2, and BCL2 were investigated. CCAT2 rs6983267 was associated with the risk of CRC per se (p < 0.01). Statistically significant interactions were found between intake of red and processed meat and CCAT2 rs6983267, TP53 rs1042522, LPCAT1 rs7737692, SLC25A20 rs7623023 (pinteraction = 0.04, 0.04, 0.02, 0.03, respectively), and the use of NSAID and alcohol intake and TP53 rs1042522 (pinteraction = 0.04, 0.04, respectively) in relation to the risk of CRC. No other consistent associations or interactions were found. This study replicated an association of CCAT2 rs6983267 with CRC and an interaction between TP53 rs1042522 and NSAID in relation to CRC. Interactions between genetic variants in fatty acid metabolism and NSAID pathways and the intake of red and processed meat were found. Our results suggest that meat intake and NSAID use affect the same carcinogenic mechanisms. All new findings should be sought replicated in independent prospective studies. Future studies on the cancer-protective effects of aspirin/NSAID should include gene and meat assessments.
Project description:<h4>Purpose</h4>Accumulating evidence demonstrates that genetic susceptibility genes can be used as biomarkers to assess sepsis susceptibility, and genetic variation is associated with susceptibility and clinical outcomes in patients with sepsis and inflammatory disease. Although studies have shown that the lncRNA <i>CCAT2</i> is involved in inflammatory diseases, it remains unclear whether <i>CCAT2</i> gene polymorphisms are associated with susceptibility to inflammatory diseases, such as sepsis, in children.<h4>Methods</h4>We genotyped the rs6983267 <i>CCAT2</i> polymorphism in 474 cases (pediatric sepsis) and 678 controls using TaqMan methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of associations.<h4>Results</h4>Our results indicate that the rs6983267 T > G polymorphism is significantly associated with an increased risk of sepsis in children (TG and TT: adjusted OR = 1.311, 95% CI = 1.016-1.743, GG and TT: adjusted OR = 1.444, 95% CI = 1.025-2.034 dominant model: GG/TG vs TT adjusted OR = 1.362, 95% CI = 1.055-1.756). Furthermore, the risk effect was more pronounced in children younger than 60 months who were male and who had sepsis.<h4>Conclusion</h4>We found that the <i>CCAT2</i> gene polymorphism rs6983267 T > G may be associated with an increased risk of pediatric sepsis in southern China. A larger multicenter study should be performed to confirm these results.
Project description:Purpose:Gastric cancer (GC) is one of the most common cancers in the world. Recently, several studies have suggested that single-nucleotide polymorphisms (SNPs) of long noncoding RNA (lncRNA) are associated with GC risk. However, the association of the lncRNA highly upregulated in liver cancer (HULC) SNP with GC risk is not yet known. The aims of this study were to evaluate the association between HULC rs7763881 SNP and the risk of GC and GC subgroups via a case-control study. Patients and Methods:rs7763881 was genotyped using TaqMan genotyping assay with 459 GC patients and 379 controls. Results:A significant association between HULC rs7763881 SNP and GC risk was not found. However, after adjustment for age and gender, the rs7763881 recessive model (CC) showed a significant association with an increased GC risk in the undifferentiated (odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17-2.94, P = 0.009), diffuse-type GC (OR = 1.72, 95% CI = 1.05-2.82, P = 0.033), LNM-positive (OR = 2.02, 95% CI = 1.24-3.27, P = 0.004), T3/T4 (OR = 1.75, 95% CI = 1.05-2.91, P = 0.032), and tumor stage III (OR = 2.01, 95% CI = 1.17-3.45, P = 0.011) subgroups when compared to the rs7763881 combined genotypes (AA+AC). Furthermore, after adjusting for age and gender, the rs7763881 additive model (CC) indicated a significantly higher GC risk than rs7763881 AA genotype in the undifferentiated (OR = 1.96, 95% CI = 1.15-3.32, P = 0.013), diffuse-type GC (OR = 2.08, 95% CI = 1.23-3.52, P = 0.004), and LNM-positive (OR = 2.00, 95% CI = 1.14-3.49, P = 0.016) subgroups. Conclusion:Our findings suggest that the HULC rs7763881 SNP is associated with increased susceptibility to GC. However, further studies are required to validate our results in large populations as well as different ethnic groups.
Project description:<h4>Background</h4>Long noncoding RNA single nucleotide polymorphisms (lncRNA-SNPs) PCAT1 rs710886, PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region present generalizability in the susceptibility to multiple cancers, however, the influence of rs710886, rs1456315 and rs6983267 on lung cancer has not been assessed. The aim of this study was to investigate associations between three lncRNA-SNPs and lung cancer.<h4>Methods</h4>A case-control study was performed on 438 patients with lung cancer and 456 healthy controls in the Han population from southern China. The collected samples were genotyped by the TaqMan genotyping, and the association with clinical characteristics, including age, gender, drinking status, smoking status, pathological types and clinical stages were analyzed. And the SNP function prediction was based on lncRNASNP2, RNAfold and GTEx.<h4>Results</h4>The rs1456315 T allele increased the risk of lung cancer [OR=1.95, 95% CI (1.58-2.43), <i>P</i>=0.003] compared to the rs1456315 C allele, and rs1456315 significantly increased the risk of lung cancer in the dominant model [OR=1.86, 95% CI (1.16-3.00), <i>P</i>=0.002]. The rs6983267 G allele, compared with the T allele, increased the risk of lung cancer [OR=1.29, 95% CI (1.07-1.57), <i>P</i>=0.007], and rs6983267 was identified as a risk factor for lung cancer [OR=1.28, 95% CI (1.06-1.55), <i>P</i>=0.003] in the additive model. Both rs1456315 and rs6983267 demonstrated significance after adjusting for the smoking status, drinking status and age. The structure prediction found rs6983267 and rs1456315 influence the secondary structure of its lncRNA. The results from lncRNASNP2 indicated that rs6983267 and rs1456315 change gain/loss target of miRNAs.<h4>Conclusion</h4><i>PRNCR1</i> rs1456315 and <i>CCAT2</i> rs6983267 on 8q24 region are significantly associated with lung cancer in the Han population of southern China and alter the potential biological function in bioinformatic analysis, and the results further extended generalism of the susceptibility of cancer-associated lncRNA-SNPs to lung cancer and underlying mechanism involved in lung cancer.
Project description:The role of long noncoding RNAs (lncRNAs) in the epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify an lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA. Expression profiling of lncRNAs revealed that highly upregulated in liver cancer (HULC) was highly expressed, and induced, by transforming growth factor-? in PDAC cells and their EVs. Knockdown of HULC decreased PDAC cell invasion and migration by inhibiting the EMT. Thus, HULC could be transferred by EVs, and promote EMT, invasion, and migration in recipient PDAC cells. To assess the roles of HULC, PDAC cell xenografts in nude mice were established. Knockdown of HULC in PDAC cells implanted in mice inhibited tumor growth. Moreover, microRNA-133b suppressed PDAC cell invasion and migration by inhibiting the EMT through targeting HULC. Furthermore, serum samples were obtained from 20 PDAC and 22 intraductal papillary mucinous neoplasm (IPMN) patients, as well as 21 healthy individuals. Analysis of serum EV HULC expression by digital PCR showed that HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. Additionally, HULC showed good predictive performance for discriminating PDAC, suggesting that the analysis of EV-encapsulated HULC would contribute to the diagnosis for human PDAC. Extracellular vesicle-transported HULC promotes cell invasion and migration by inducing the EMT, and microRNA-133b suppresses the EMT by targeting HULC. Extracellular vesicle-encapsulated HULC could be a potential circulating biomarker for human PDAC.
Project description:The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
Project description:Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68-0.86; rs1105879 OR = 0.77 95% CI = 0.69-0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk.