Association between miR-34b/c rs4938723 polymorphism and risk of cancer: An updated meta-analysis of 27 case-control studies

Several studies investigated the association between miR-34b/c rs4938723 polymorphism and the risk of several human cancers, but the findings remain inconclusive. To evaluate the impact of miR-34b/c rs4938723 on cancer risk, we performed a meta-analysis on all available studies including 12 361 cancer cases and 14 270 controls. Eligible studies were identified by searching PubMed, Web of Science, Scopus, and Google scholar databases. Pooled odds ratios with 95% confidence intervals were calculated in codominant, dominant, recessive, overdominant, and allele models to quantitatively estimate the association. The overall findings showed no significant association between miR-34b/c rs4938723 polymorphism and cancer risk in codominant, dominant, recessive, overdominant, and allele inheritance model. However, in stratified analysis by cancer types, the rs4938723 polymorphism significantly increased the risk of gastrointestinal cancer, hepatocellular carcinoma. In addition, the rs4938723 polymorphism was associated with decreased risk of esophageal squamous cell carcinoma, colorectal cancer, and acute lymphoblastic leukemia. The findings did not support an association between rs4938723 variant and digestive tract as well as gastric cancer. In summary, the findings of this meta-analysis indicated that the miR-34b/c rs4938723 polymorphism might be associated with some cancer development. Larger and well-designed studies are necessary to estimate this association in detail.     

Mitochondrial DNA haplogroup M7 confers a reduced risk of colorectal cancer in a Han population from northern China

Mitochondria are central eukaryotic organelles in cellular metabolism and ATP production. Mitochondrial DNA (mtDNA) alterations have been implicated in the development of colorectal cancer (CRC). However, there are few reports on the association between mtDNA haplogroups or single nucleotide polymorphisms (SNPs) and the risk of CRC. The mtDNA of 286 Northern Han Chinese CRC patients were sequenced by next-generation sequencing technology. MtDNA data from 811 Han Chinese population controls were collected from two public data sets. Then, logistic regression analysis was used to determine the effect of mtDNA haplogroup or SNP on the risk of CRC. We found that patients with haplogroup M7 exhibited a reduced risk of CRC when compared to patients with other haplogroups (odds ratio [OR] = 0.532, 95% confidence interval [CI] = 0.285–0.937, p = 0.036) or haplogroup B (OR = 0.477, 95% CI = 0.238–0.916, p = 0.030). Furthermore, haplogroup M7 was still associated with the risk of CRC when the validation and combined control cohort were used. In addition, several haplogroup M7 specific SNPs, including 199T>C, 4071C>T and 6455C>T, were significantly associated with the risk of CRC. Our results indicate the risk potential of mtDNA haplogroup M7 and SNPs in CRC in Northern China.     

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population

Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C<A) genes has been reported on Bangladeshi population relating those with colorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR = 2.58, 95% CI = 1.77–3.77, p < 0.05) and Pro/Pro mutant homozygosity (adjusted OR = 2.92, 95% CI = 1.78–4.78, p < 0.05) along with the combined genotype (Arg/Pro + Pro/Pro) (adjusted OR = 2.70, 95% CI = 1.90–3.82, p < 0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p < 0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR = 2.02, 95% CI = 1.42–2.87, p < 0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population.     

Investigation of the VDR gene polymorphisms association with susceptibility to colorectal cancer

The effects of 1,25-dihydroxyvitamin D3 are mediated by binding to a specific intracellular vitamin D receptor (VDR), which has been identified in a variety of tissues. Certain polymorphisms in the VDR gene have been associated with various neoplasms. For this purpose, we studied whether VDR TaqI or FokI genotype are associated with serum 25-hydroxyvitamin D3 in 52 controls and 26 patients with colorectal cancer. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), and agarose gel electrophoresis tecniques were used to detect these polymorphisms. We measured 25-hydroxyvitamin D3 serum levels by ELISA. The frequencies of the FF, Ff and ff genotypes were 73.1%, 11.5%, 15.4% in colorectal cancer patients and 38.5%, 59.6%, 1.9% in healthy controls, respectively. We observed the T allele in 50% and 58.7%, and the t allele in 50% and 41.3% of colorectal cancer patients and the control group, respectively. In patients with colorectal cancer who have TT genotype, serum 25-hydroxyvitamin D3 level was lower than those with Tt/tt genotype (p:0.016). The frequency of subjects with TTFf or TtFf genotype in colorectal cancer patients was very low compared with all other genotypes (OR = 0.112; 95%CI 0.030-0.419). These data suggest that VDR TtFf or TTFf genotypes may protect against colorectal carcinogenesis. However, further studies are necessary to confirm these findings.     

miRNA-143 replacement therapy harnesses the proliferation and migration of colorectal cancer cells in vitro

miR-143 is a tumor suppressor miRNA which its downregulation is frequently reported in colorectal cancer (CRC). This miRNA is a negative regulator of K-RAS, c-MYC, BCL-2, and MMP-9 genes which are engaged in tumor growth and metastasis. In the present study, miR-143 restoration was performed by transfection of the pCMV-miR-143 vector into the SW-480 CRC cells. Subsequently, alterations in proliferative and migratory potential of the cells were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and wound-healing assays, respectively. Moreover, to detect apoptosis incidence in the transfected cells, 4',6-diamidino-2-phenylindole (DAPI) staining was used. Furthermore, mRNA levels of c-MYC, K-RAS, MMP-9, and BCL-2, as potential targets of miR-143, were assessed by quantitative Real-Time PCR (qRT-PCR). Also the expression levels of c-MYC, K-RAS, and MMP-9 proteins were investigated by the western blot analysis. Finally, the ratio of BAX to BCL-2 expression, as a potential marker of the response to apoptosis stimuli, was compared between the control and test groups. Furthermore, the trypan blue test was performed to determine the cell viability in cell suspension. According to the results, a decreased viability and migratory potential was observed for the miR-143 receiving cells. The DAPI staining also confirmed the occurrence of apoptosis. Moreover, BCL-2, K-RAS, MMP-9, and c-MYC mRNAs were significantly downregulated in the miR-143 grafted cells. The BAX/BCL-2 ratio also indicated a notable increase in the cells with miR-143 overexpression. In brief, miR-143 replacement could be considered as an effective strategy for the management of CRC and attenuating its invasive features.     

The association of VEGF rs833061 and rs2010963 polymorphisms with susceptibility to colorectal cancer in an Iranian population

Vascular endothelial growth factor (VEGF) is one of the most important regulators of angiogenesis. Several single nucleotide polymorphisms (SNPs) are associated with the VEGF overexpression and tumor progression in several cancers. This study aimed to determine the association of VEGF rs833061 and rs2010963 polymorphism and their haplotypes with susceptibility to colorectal cancer (CRC) in the Iranian population. A total of 284 colorectal cancer patients (37.3% women, 62.7% men) were enrolled in this study. Healthy controls without evidence of cancer history or family cancer predispositions were frequency-matched to the cases by sex and age (± 5 years). Genotyping was performed by the Sequenom mass ARRAY method and the genotype distribution and risk estimate were analyzed by SPSS software. The correlation between the genotypes and clinicopathological parameters (Dukes stage, phenotype, location, differentiation, and tumor size) among colorectal cancer patients were investigated. We found a significant relationship, between rs833061T/C genotype and their TG haplotype with the age of diagnosis < 60; (p = 0.012, p = 0.014) and rs2010963G/C genotype with female gender and TG haplotype with third and fourth tumor stage and tumor location (p = 0.04and p = 0.047). This study showed that rs833061T/C genotype and TG haplotype increase the susceptibility to colon cancer in the Iranian population. This susceptibility has a significant relationship with the age of diagnosis and different stages of the tumor.     

Association analysis between MDR1 gene polymorphisms and risk of hepatocellular carcinoma in Chinese population

Objective: XRCC4 play a key role in nonhomologous end-joining repair pathway. Alterations in DNA repair gene have been shown to reduce DNA repair capacity thereby inflicting carcinogenesis.

Methods: In a hospital-based case-control study, 192 prostate cancer (PCa) and 224 healthy controls. They were genotyped for XRCC4 G-1394T (rs6869366), intron 3 (rs28360071) intron 7 (rs28360317) and intron 7 (rs1805377), polymorphisms using polymerase chain reaction–restriction fragment length polymorphism.

Result: Carriers of GG genotype of rs6869366 were at reduced risk. Del/Del of rs28360071 and 28360317 demonstrated increased risk. The haplotype analysis was observed to be associated with a significant increase in PCa risk. Combined genotype of rs6869366, rs28360071 and rs1805377 have shown significant risk with high Gleason grade.

Conclusion: Our results suggested that the variant genotype of XRCC4 rs28360071 and rs28360317 and haplotype analysis may be associated with PCa risk.     

PUNISHER rs12318065 C>A transversion: a putative somatic driver mutation for poor prognosis in colon cancer

Objective: Colon cancer (CC) remains one of the leading causes of cancer death worldwide. Several mutations/polymorphisms have been implicated in CC development and/or progression. The role of the recently identified variants related to the long non-coding RNAs (lncRNAs) family has not yet been fully uncovered. In this sense, we aimed to explore the association between the lncRNA PUNISHER rs12318065 variant and the CC risk and/or prognosis. Methods: A total of 408 CC (paired 204 cancer/non-cancer) tissues were genotyped using the TaqMan allelic discrimination assay. Results: “A” variant was associated with higher susceptibility to develop CC under heterozygote (A/C vs. C/C: OR = 1.39, 95%CI = 1.09–2.17, P=0.002), homozygote (A/A vs. C/C: OR = 2.63, 95%CI = 1.51–4.58, P=0.001), dominant (A/C-A/A vs. C/C: OR = 1.72, 95%CI = 1.15–02.57, P=0.008), and recessive (A/A vs. C/C-A/C: OR = 2.23, 95%CI = 1.34–3.72, P=0.001) models. Patients with metastasis were more likely to harbor A/A and A/C genotypes (16.7% and 14.1%) than 11% with the C/C genotype (P=0.027). Patients harboring C>A somatic mutation were more likely to develop relapse (52.6% vs. 26.5%, P=0.003), have poor survival (57.9% vs. 27.7%, P=0.001), and have shorter disease-free survival (43.2 ± 2.6 months vs. 56.8 ± 1.29 months, P<0.001) and overall survival (49.6 ± 2.4 months vs. 56.6 ± 0.99 months, P<0.001). Multivariate Cox regression analysis showed that patients with distal metastasis and C>A somatic mutation were three times more likely to die. Conclusions: To our knowledge, the present study is the first to identify that the PUNISHER rs12318065 variant could be a novel putative driver of colon cancer and is associated with poor prognosis.     

Functional implications of miR-145/RCAN3 axis in the progression of cervical cancer

Cervical cancer, as the second leading cause of death in women malignant tumor, is not optimistic about survival rate and late recurrence rate. RCAN3 has been reported to function in a variety of diseases, but its relationship with cervical cancer has not been reported. This study aimed to investigate whether RCAN3 contributes to the development of cervical cancer and its mechanism. RCAN3 expression was analyzed in 306 cervical cancer tissues and 13 normal healthy tissues from TCGA and GTEX databases. Kaplan-Meier analysis and Cox regression analysis were carried out to assess the potential function of RCAN3. Subsequently, the upstream regulatory miRNA of RCAN3 was predicted by bioinformatics and confirmed using dual luciferase reporter assay. CCK-8, colony formation assay, transwell assay were used for functional analysis of miR-145/RCAN3 axis in vitro. The results showed that RCAN3 was highly expressed in cervical cancer tissues, leading to poor prognosis, and could be used as a prognostic factor for cervical cancer. MiR-145 directly targeted RCAN3, which was lowly expressed in cervical cancer tissues and cell lines, and the higher the miR-145 expression, the longer the survival time of patients. Finally, from the functional experiments results we can see that miR-145 can inhibit the proliferation, migration and invasion of cervical cancer cells, but overexpression of RCAN3 can reverse miR-145-mediated inhibition. To sum up, miR-145/RCAN3 axis may serve as a potential therapeutic target to regulate the progression of cervical cancer.     

The clinical significance of circulating miR-21, miR-142, miR-143, and miR-146a in patients with prostate cancer

BackgroundProstate cancer (PCa) is the most common type of solid tissue cancer among men in western countries. In this study, we determined the levels of circulating miR-21, miR-142, miR-143, miR-146a, and RNU 44 levels as controls for early diagnosis of PCa.MethodsThe circulating miRNA levels in peripheral blood samples from 43 localized PCa patients, 12 metastatic PCa (MET) patients, and a control group of, 42 benign prostate hyperplasia (BPH) patients with a total of 97 volunteers were determined the by PCR method.ResultsNo differences in the DCT values were found among the groups. In PCa and PCaMet groups the expression of miR21 and miR142 were higher compared to the BHP group. No other differences were observed among the other groups. miR21 expression in the PCa group was 6.29 folds upregulated whereas in the PCaMet group 10.84 folds up-regulated. When the total expression of miR142 is evaluated, it showed a positive correlation with mir21 and mir 146 (both p<0.001). Also, the expression of miR146 shows a positive correlation with both miR21 and miR143 (both p<0.001). Expression of miRNAs was found to be an independent diagnostic factor in patients with Gleason score, PSA, and free PSA levels.ConclusionsOur study showed that co-expression of miR21, miR-142, miR-143, and miR-146a and the upregulation of miR-21 resulted in increased prostate carcinoma cell growth. In the PCaMet group, miR21 is the most upregulated of all miRNAs. These markers may provide a novel diagnostic tool to help diagnose PCa with aggressive behavior.     

Association of leptin and leptin receptor gene polymorphisms with systemic lupus erythematosus in a Chinese population

To explore the association of LEP and leptin receptor (LEPR) gene single‐nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. Four LEP SNPs (rs11761556, rs12706832, rs2071045 and rs2167270) and nine LEPR SNPs (rs10749754, rs1137100, rs1137101, rs13306519, rs8179183, rs1805096, rs3790434, rs3806318 and rs7518632) were genotyped in a cohort of 633 patients with SLE and 559 healthy controls. Genotyping of SNPs was performed with improved multiple ligase detection reaction (iMLDR). No significant differences were detected for the distribution of allele and genotype frequencies of all 13 SNPs between patients with SLE and controls. The genotype effects of recessive, dominant and additive models were also analysed, but no significant evidence for association was detected. However, further analysis in patients with SLE showed that the TT genotype and T allele frequencies of the LEP rs2071045 polymorphism were nominally significantly higher in patients with pericarditis (P = 0.012, P = 0.011, respectively). In LEPR, the GA/AA genotype and A allele frequencies of the rs1137100 polymorphism were both nominally associated with photosensitivity in patients with SLE (P = 0.043, P = 0.018, respectively). Moreover, the genotype and allele distribution of rs3806318 were also nominally associated with photosensitivity in patients with SLE (P = 0.013, P = 0.008, respectively). No significant differences in serum leptin levels were observed in patients with SLE with different genotypes. In summary, LEP and LEPR SNPs are not associated with genetic susceptibility to SLE, but may contribute to some specific clinical phenotype of this disease; further studies are necessary to elucidate the exact role of LEP and LEPR genes in the pathogenesis of SLE.     

Lack of association between polymorphisms in the P2X7 gene and tuberculosis in a Chinese Han population

Several studies have suggested that genetic factors may affect the susceptibility of a population to tuberculosis, and it has been found that P2X7 is linked to an increased risk for tuberculosis in some West African, Southeast Asian, North American, and North European populations. To explore the potential role of P2X7 in the susceptibility to tuberculosis among members of the Chinese Han population, we evaluated the association of the 1513A→C and −762T→C polymorphisms in P2X7 with the risk for tuberculosis. PCR amplification of genomic DNA was followed by restriction fragment length polymorphism analysis, and allele-specific PCR was used. We found no significant differences in the genotypic and allelic frequencies of 1513A→C polymorphisms in 96 patients with tuberculosis compared with 384 control subjects [ P =0.856 and 0.316, respectively; odds ratio (OR) for the C allele=0.976; 95% confidence interval (CI)=0.755–1.262]. Similarly, no significant association was found between the −762T→C polymorphism and tuberculosis ( P =0.102 and 0.095 for the patients and controls, respectively; OR for the C allele=0.924; 95% CI=0.847–1.010). Thus, our analysis of P2X7 showed that the 1513A→C and −762T→C polymorphisms did not appear to be associated with the susceptibility of the Chinese Han population to tuberculosis.     

Association of MCP-1 promoter polymorphism with susceptibility to nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is prevalent among populations from southern China and is influenced by both genetic and environmental risk factors. The monocyte chemoattractant protein-1 (MCP-1), a member of cysteine-cysteine chemokine family, plays critical roles in cancers. A polymorphism within the MCP-1 promoter, rs1024611, has been shown to be significantly associated with the risk of several cancers. Our purpose was to assess the role of rs1024611 in NPC susceptibility. By polymerase chain reaction-restriction fragment length polymorphism method, we genotyped rs1024611 in 593 patients with NPC (cases) and 480 cancer-free subjects (controls) among Guangxi population from southern China. We observed that the G allele of rs1024611 was significantly associated with the increased risk of NPC in an additive model and dominant model, respectively (P = 0.018 and 0.010, odds ratio = 1.25 and 1.41, respectively). No appreciable variation of the effects was found across the subgroups stratified by age, sex, nationality, smoking and drinking status, and smoking level. In addition, significantly higher messenger RNA (mRNA) expression level of MCP-1 was observed in NPC tissues than that in normal nasopharyngeal tissues, and the G allele of rs1024611 was significantly associated with elevated mRNA expression level of MCP-1 in Epstein-Barr virus-transformed lymphocytes. In conclusion, our findings suggested that rs1024611 at the MCP-1 promoter may be a risk factor for NPC. Further studies with larger sample size are necessary to confirm these findings.     

Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan

The relationship between diet and colorectal cancer has been previously demonstrated and supported with strong epidemiological evidence. The role of genetic polymorphisms has, however, been less well elaborated upon. We conducted a hospital-based case–control study including 727 cases and 736 healthy controls to evaluate the associations of the polymorphic phase-I and -II biotransformations (CYP1A1, CYP1A2, GSTM1, GSTT1, GSTP1, NAT1 and NAT2) and DNA-repair enzymes (XRCC1, XRCC3 and XPD) with the risk of contracting colorectal cancer. We found that men featuring the CYP1A1*2C G/G genotype, the GSTT1 null genotype and XPD 751 with the Gln allele were associated with an elevated risk of colorectal cancer than were men who did not exhibit such genetic features. Multivariate logistic regression analysis revealed that individuals featuring more than two high-risk genotypes increased the colorectal-cancer risk 3.1-fold (OR = 3.1, 95% CI = 1.8–5.2). For women, subjects featuring the CYP1A1*2C G/G genotype and the XRCC3 Thr/Thr genotype faced a 3.1-fold greater risk (95% CI = 1.3–7.0) of colorectal cancer when compared to those featuring the CYP1A1*2C A allele and the XRCC3 Met allele. Taken together, this study suggests that polymorphisms of genes involved in biotransformation and DNA repair could modulate colorectal-cancer risk in Taiwan.     

Association of excision repair cross-complimentary group 1 gene polymorphisms with breast and ovarian cancer susceptibility

The role of excision repair cross-complimentary group 1 (ERCC1) gene polymorphisms in breast and ovarian cancer development has long been controversial and existing data were inconsistent. Here, we conducted a comprehensive meta-analysis to better clarify the association. Case-control studies published from December 2008 to November 2018 were assessed. The statistical analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. Fifteen articles with 24 case-control studies and 3 ERCC1 polymorphisms were enrolled. A total of 20 923 participants including 9896 cases and 11 027 controls were analyzed. The results showed that C to T variation in the ERCC1 rs11615 (C/T) polymorphisms was correlated with breast cancer susceptibility (T vs C: OR = 1.19, 95% CI = 1.02-1.38; TT + CT vs CC: OR = 1.24, 95% CI = 1.12-1.36). ERCC1 rs3212986 (C/A) polymorphisms posed an increased risk for breast and ovarian cancer as whole (A vs C: OR = 1.12, 95% CI = 1.01-1.25; AA + CA vs CC: OR = 1.11, 95% CI = 1.02-1.22), and presented especially higher risk for ovarian cancer (A vs C: OR = 1.31, 95% CI = 1.05-1.63; AA vs CA + CC: OR = 1.66, 95% CI = 1.12-2.47; AA vs CC: OR = 1.72, 95% CI = 1.12-2.64). Meanwhile, neither overall group analyses nor stratified analyses displayed any association of ERCC1 rs2298881 (A/C) polymorphisms in breast and ovarian cancer susceptibility. This meta-analysis suggested that ERCC1 rs11615 (C/T) polymorphisms were associated with breast cancer susceptibility and rs3212986 (C/A) polymorphisms were especially correlated with ovarian cancer risk. More case-control studies with well-adjusted data and diverse populations are essential for validation of our conclusion.