The clinicopathological characteristic associations of long non-coding RNA gene H19 polymorphisms with uterine cervical cancer.
ABSTRACT: The purposes of the current study were conducted to explore the relationships among long non-coding RNA gene H19 (LncRNA H19) polymorphisms and clinicopathological characteristics of uterine cervical cancer, and patient prognosis in Taiwan. Five genetic variants of LncRNA H19 rs3024270, rs2839698, rs3741219, rs2107425 and rs217727 were recruited from one hundred and thirty-four patients with invasive cancer, 101 with high-grade cervical intraepithelial neoplasia (CIN) of uterine cervix and 325 controls and their genetic distributions were determined. It indicated no associations of these LncRNA H19 genetic variants with development of cervical cancer. CC/CT in LncRNA H19 rs2839698 exhibited less risk to have pelvic lymph node metastasis [Odds ratio (OR): 0.19, 95% Confidence interval (CI):0.04-0.82, p=0.028)], as compared with TT. Meanwhile, cervical cancer patients with AA/AG in rs3741219 also had less risk to develop pelvic lymph node metastasis (OR: 0.17, 95% CI: 0.05-0.63, p=0.008), large tumor (OR: 0.17, 95% CI: 0.04-0.82, p=0.014) as well as parametrium (OR: 0.26, 95% CI: 0.07-0.95, p=0.045) and vagina invasion (OR: 0.25, 95% CI: 0.07-0.91, p=0.041, as compared to those with GG. However, only positive pelvic lymph node metastasis was related to worse recurrence-free survival and poor overall survival. Conclusively, it indicated no association of LncRNA H19 SNPs with cervical carcinogensis in Taiwanese women. Although genotypes TT in LncRNA H19 rs2839698 and GG in rs3741219 are related to some poor clinicopathological parameters of cervical cancer, only pelvic lymph node status could predict 5 year patient survival significantly.
Project description:Long non-coding RNA (lncRNA) H19 is involved in tumor development, progression, and metastasis. This case-control study assessed the association between H19 genetic variants and susceptibility to gastric cancer (GC) in a Chinese Han population. We genotyped four lncRNA H19 single nucleotide polymorphisms (SNPs) (rs217727 C > T, rs2839698 C > T, rs3741216 A > T, rs3741219 T > C) in 500 GC patients and 500 healthy controls. Carriers of variant rs217727T and rs2839698T alleles showed increased GC risk (P = 0.008 and 0.011, respectively). Compared with the common genotype, CT + TT rs217727 and CT + TT rs2839698 genotypes were associated with significantly increased GC risk (P = 0.040, adjusted odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.01-1.71; P = 0.033, adjusted OR = 1.31, 95% CI = 1.02-1.69, respectively). Further stratified analyses revealed that the association between GC risk and variant genotypes of rs217727 was more profound in younger individuals (?59 years) and non-smokers, while the association between risk and the rare rs2839698 genotype persisted in men and rural subjects. rs2839698 CT and TT genotypes were also associated with higher serum H19 mRNA levels compared with the CC genotype. These findings suggest that lncRNA H19 SNPs may contribute to susceptibility to GC.
Project description:BACKGROUND:Long non-coding RNA (lncRNA) H19 is involved in the carcinogenesis, progression, and metastasis of colorectal cancer (CRC). Recently, a few studies explored the relationship between lncRNA H19 gene rs2839698 polymorphism and CRC risk, but with conflicting findings. MATERIALS AND METHODS:A case-control study with 315 CRC cases and 441 controls was designed in a Chinese population. Genotyping was performed using PCR-RFLP. RESULTS:It was found rs2839698 polymorphism was associated with a decreased risk of CRC (AA vs GG: OR, 0.73; 95% CI, 0.54-0.98; P = .037; A vs G: OR, 0.78; 95% CI, 0.63-0.96; P = .021). Stratified analyses indicated this positive association was also significant in the non-smokers (AA vs GG: OR, 0.49; 95% CI, 0.25-0.93; P = .029), non-drinkers, those aged ? 60 years, and overweight individuals (BMI ? 24). In addition, rs2839698 polymorphism was also related to the lymph node metastasis (AA vs GG: OR, 0.43; 95% CI, 0.21-0.88; P = .019) and tumor size (AA vs GG: OR, 0.42; 95% CI, 0.20-0.88; P = .020) for patients with CRC. CONCLUSION:To sum up, the lncRNA H19 gene rs2839698 polymorphism decreases the risk of CRC in Chinese individuals, especially among the non-smokers, non-drinkers, individuals aged ? 60 years, and overweight individuals (BMI ? 24). Thus, the lncRNA H19 gene rs2839698 polymorphism might be an important biomarker and diagnostic marker for predicting the susceptibility to CRC in Chinese Han population.
Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, whose diversified occurrence worldwide indicates a connection between genetic variations among individuals and the predisposition to such neoplasms. Mounting evidence has demonstrated that long non-coding RNA (lncRNA) H19 can have both promotive and inhibitory effects on cancer development, revealing a dual role in tumorigenesis. In this study, the link of H19 gene polymorphisms to hepatocarcinogenesis was assessed between 359 HCC patients and 1190 cancer-free subjects. We found that heterozygotes for the minor allele of H19 rs2839698 (T) and rs3741219 (G) were more inclined to develop HCC (OR, 1.291; 95% CI, 1.003-1.661; p = 0.047, and OR, 1.361; 95% CI, 1.054-1.758; p = 0.018, respectively), whereas homozygotes for the polymorphic allele of rs2107425 (TT) were correlated with a decreased risk of HCC (OR, 0.606; 95% CI, 0.410-0.895; p = 0.012). Moreover, patients who bear at least one variant allele (heterozygote or homozygote) of rs3024270 were less prone to develop late-stage tumors (for stage III/IV; OR, 0.566; 95% CI, 0.342-0.937; p = 0.027). In addition, carriers of a particular haplotype of three H19 SNPs tested were more susceptible to HCC. In conclusion, our results indicate an association between H19 gene polymorphisms and the incidence and progression of liver cancer.
Project description:BACKGROUND:The H19 is a maternally expressed imprinted gene transcribing a long noncoding RNA (lncRNA), which has previously been reported to be involved in tumorigenesis and cancer progression. The aim of this study was to evaluate the associations between two lncRNA-H19 (rs3741219 T>C and rs217727 C>T) gene polymorphisms with the risk of breast cancer (BC). METHODS:In a case-control investigation, we evaluated 150 BC patients and 100 cancer-free subjects in East Azerbaijan Province of Iran. To assess two gene polymorphisms, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used. RESULTS:The genotype frequencies of two lncRNA-H19 (rs217727 C>T and rs3741219 T>C) gene polymorphisms TT + TC/CC and CC + CT/TT have not shown a statistically significant association with the risk of BC (P = 0.065; OR = 0.967; 95% CI, 0.938-0.996) and (P = 0.510; OR = 1.583; 95% CI, 0.399-6.726), respectively. In addition, our findings revealed a significant differences in allele frequencies in lncRNA-H19 rs217727 C>T polymorphism between groups (P = 0.033; OR = 1.985; 95% CI, 1.048-3.761). CONCLUSION:Our findings suggested that rs217727 C>T polymorphism may be involved in the pathogenesis of BC, whereas rs3741219 T>C variation may not be involved in the genetic background of BC in Iranian.
Project description:Glioma is the most common tumor of the central nervous system; variation in susceptibility and prognosis worldwide suggests that there are molecular and genetic differences among individuals. The H19 gene plays a dual role in carcinogenesis. In this study, associations between H19 polymorphisms and susceptibility as well as prognosis in glioma were evaluated. In total, 605 patients with glioma and 1,300 cancer-free subjects were enrolled in the study. Individuals with the rs3741219 A>G allele were less likely to develop glioma (relative risk [RR] = 0.54, 95% confidence interval [95% CI] = 0.45-0.63, p < 0.001), whereas rs217727 G>A and rs2839698 G>A genotypes were not associated with glioma risk. The associations between H19 polymorphisms and prognosis were assessed, including overall survival and progression-free survival. Three focused H19 polymorphisms did not show a significant effect on survival. Further analysis based on false-positive report probability validated these significant results. In the haplotype analysis, individuals with the Grs217727Ars2839698Grs3741219 haplotype were less likely to develop glioma (odds ratio [OR] = 0.33, 95% CI = 0.23-0.46, p = 0.02). Overall, carriers of the rs3741219 AG or GG genotype of H19 have a decreased susceptibility to glioma, but polymorphisms in this gene are not related to prognosis.
Project description:H19 refers to a long non-coding RNA (lncRNA) that functions as an oncogenic molecule in different cancer cells. Genetic variants of H19 may affect the activity of certain regulatory factors, which subsequently regulate the aberrant expression of H19. This feedback loop might be one of the underlying mechanisms influencing tumour susceptibility and prognosis. Although there have been several recent studies that examined possible links between polymorphisms in H19 and cancer risk, the results have been inconclusive. Thus, we performed a meta-analysis to estimate the associations between H19 polymorphisms (rs2107425, rs2839698 and rs217727) and cancer risk. Ten studies comprising 13,392 cases and 18,893 controls were included in the study. Overall, the variant T allele of rs2107425 correlated with a significantly decreased risk of developing cancer (dominant model: OR = 0.86; 95% CI = 0.76-0.98). In addition, a marginally significant association between the rs2839698 and cancer risk was observed (dominant model: OR = 1.09; 95% CI = 0.99-1.20). After stratification for ethnicity, it became apparent that Asians with the variant A allele of rs2839698 exhibited a significantly higher risk of developing cancer (dominant model: OR = 1.11; 95% CI = 1.01-1.23). Interestingly, the rs2839698 variant was also significant associated with an increased risk of cancers of the digestive system (dominant model: OR = 1.23; 95% CI = 1.08-1.41). These findings provided evidence that H19 rs2107425 may modify general cancer susceptibility, while rs2839698 may modify cancer susceptibility based on ethnicity and type. Further experimental studies to evaluate the limits of this hypothesis are warranted, and future functional studies are required to clarify the possible mechanisms.
Project description:The long non-coding RNA (lncRNA) H19 has been demonstrated to play a crucial role in carcinogenesis, including renal cell carcinoma (RCC). However, the impact of genetic variations in H19 gene on RCC has not been investigated before. In the present study, we sought to evaluate whether genetic polymorphisms in H19 are related to the susceptibility and mortality of RCC. We genotyped four widely studied polymorphisms in H19 and assessed their relationship with susceptibility and prognosis of RCC in a case-control study compromising 1,027 cases and 1,094 controls. The functionality of the important polymorphism was further investigated by real-time polymerase chain reaction and luciferase reporter assay. We found that H19 rs2839698 was significantly associated with risk and prognosis of RCC. Compared with the H19 rs2839698 CC genotype, the variant genotypes (CT/TT) were significantly associated with increased risk of RCC (P = 0.023, OR = 1.21; 95% CI = 1.03-1.45). Besides, patients with variant genotypes (CT/TT) were more likely to develop large tumor (P = 0.003, OR = 1.47; 95% CI = 1.16-1.85) and advanced disease (P = 0.010, OR = 1.59; 95% CI = 1.12-2.26); and had a significantly unfavorable overall survival than those with the rs2839698 CC genotype (CT/TT vs. CC: Log-rank P = 0.026, HR = 2.25, 95%CI = 1.07-4.75). Furthermore, the CT/TT genotypes were associated with significantly increased expression of H19 in renal tissue. The luciferase reporter assays revealed the potential effect of rs2839698 variant on the binding of microRNAs to H19. Our results suggest that the H19 rs2839698 variant may be a genetic predictor of susceptibility and mortality of RCC. The risk effects and the functional impact of the variant on H19 still need further validation.
Project description:BACKGROUND:H19, a well-known long non-coding RNA, is involved in carcinogenesis and progression of multiple cancers. Molecular epidemiological research suggests that polymorphisms in H19 are associated with an increased risk of cancer, but the results are inconsistent. Thus, we performed a meta-analysis to estimate the associations between H19 polymorphisms and cancer susceptibility. METHODS:PubMed, Embase, and Web of Science databases were searched. Odds ratios with 95% confidence interval were applied to assess the association between H19 rs2107425, rs217727, rs2839698, rs2735971, rs3024270, and rs3741219 polymorphisms and cancer susceptibility in all 5 models. We also predicted the H19 secondary structure, as well as the generation and abolishment of miRNA binding sites on H19 through the selected SNPs. RESULTS:Eighteen related studies, involving 17,090 patients and 23,532 control samples, were analyzed. The pooled data showed that rs2839698 polymorphism was significantly associated with an increased cancer susceptibility. As for rs217727 and rs3024270 polymorphisms, similarly increased risks were found in specific genetic models and stratified groups. However, significant decreases in cancer risk were observed for rs2107425 and rs2735971 in the total population, as well as in subgroup analyses. In addition, no significant associations were found in all 5 models for rs3741219 polymorphism. Furthermore, RNAfold prediction revealed that the centroid secondary structure was markedly altered in rs217727 and rs2735971. We also identified that rs217727 G>A and rs2839689 G>A alleles could create and destroy miRNA binding sites on H19. CONCLUSION:The results of our meta-analyses suggest that H19 polymorphisms may be associated with the risk of cancer development.
Project description:Hepatocellular cancer (HCC) is one of the major causes of cancer-related mortality. Genetic polymorphisms may affect the susceptibility and clinical outcomes of cancers. We aim to manifest the association of single nucleotide polymorphisms (SNPs) of lncRNA-H19 gene with the risk and prognosis of HCC. A total of 944 samples composed of 472 HCC patients and 472 matched controls were included in the risk analysis and amongst them 350 HCC samples were investigated in the prognosis analysis. KASP method was conducted for the SNP genotyping. The TT + CT genotype of rs2839698 was found to be associated with a 1.32-fold increased HCC risk (P=0.037, 95% confidence interval (CI) = 1.02-1.70). In the stratified analysis, rs2839698 (odds ratio (OR) = 1.57, P=0.007, 95% CI = 1.13-2.18) and rs3024270 (OR = 1.71, P=0.019, 95% CI = 1.09-2.68) were found to show more obvious increased HCC risk in the age ?60 subgroup. And we found that rs2839698 showed an increased HCC risk in the ever smoking subgroup. But in the male subgroup of rs2735971, it showed a decreased HCC risk. Furthermore, haplotype analysis showed that rs2735971-rs2839698-rs3024270 G-T-C significantly increased the risk of HCC (OR = 1.23, 95% CI = 1.01-1.51, P=0.043). Multilogistic analysis revealed no significant results of the interaction effects of the SNPs and environment factors. And in our study, rs2839698 showed a significant poor prognosis in the ever smoking subgroup (hazard rate (HR) = 5.19, 95% CI = 1.12-24.07, P=0.035). lncRNA-H19 rs2839698 SNP has the potential to be predictors for HCC risk and prognosis.
Project description:Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early stage cervical cancer. Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early stage cervical cancer patients was performed for representatives of the identified pathways. Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N0, and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P<0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3 and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N0 (OR:0.20, 95%CI:0.06-0.66) and the β-catenin pathway (p120 positivity) to N+ (OR:1.79, 95%CI:1.05-3.05). Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated non-canonical β-catenin pathways are important in pelvic lymph node metastasis in early stage cervical cancer. Overall design: For the microarray experiment, we selected fresh frozen primary cervical cancer tissue, containing at least 80% tumor cells, of patients with histologically confirmed N0 (n=20) and of patients with N+ (n=19). The N0 and N+ groups were matched for age, FIGO stage and histology (all squamous cell carcinoma).