Increased levels of the long intergenic non-protein coding RNA POU3F3 promote DNA methylation in esophageal squamous cell carcinoma cells.

BACKGROUND & AIMS: Thousands of long intergenic non-protein coding RNAs (lincRNAs) have been identified in mammals via genome-wide sequencing studies. Many are functional, but are expressed aberrantly by cancer cells. We investigated whether levels of lincRNAs are altered during the development of esophageal squamous cell carcinoma (ESCC). METHODS: We used quantitative real-time polymerase chain reaction to measure levels of 26 highly conserved lincRNAs in ESCC and surrounding nontumor tissues. A total of 182 ESCC and paired adjacent nontumor tissue samples were collected from patients undergoing tylectomy at The First Affiliate Hospital of Soochow University from 2001 through 2009; another 178 ESCC tissue pairs were collected from Guangzhou Medical University from 2002 through 2009. LincRNAs were expressed from lentiviral vectors or knocked down with small hairpin RNAs in Eca-109 and TE-1 cells. RESULTS: Levels of a lincRNA encoded by a gene located next to POU3F3 (linc-POU3F3) were significantly higher in ESCC than neighboring nontumor tissues. In RNA immunoprecipitation assays, linc-POU3F3 was associated with the EZH2 messenger RNA (mRNA). Overexpression of linc-POU3F3 in cell lines increased their proliferation and ability to form colonies, and reduced the expression of POU3F3 mRNA, whereas knockdown of linc-POU3F3 increased the levels of POU3F3 mRNA. CpG islands in POU3F3 were densely hypermethylated in cell lines that overexpressed linc-POU3F3; methylation at these sites was reduced by knockdown of linc-POU3F3. Pharmacologic inhibition of EZH2 increased the levels of POU3F3 mRNA and significantly reduced binding of DNA methyltransferase (DNMT)1, DNMT3A, and DNMT3B to POU3F3. ESCC cells with knockdown of linc-POU3F3 formed xenograft tumors more slowly in mice than control ESCC cells. CONCLUSIONS: Levels of linc-POU3F3 are increased in ESCC samples from patients compared with nontumor tissues. This noncoding RNA contributes to the development of ESCC by interacting with EZH2 to promote methylation of POU3F3, which encodes a transcription factor.

Functional polymorphisms in the CD44 gene and acute myeloid leukemia cancer risk in a Chinese population.

CD44 is such one adhesion molecule that mediates interactions between acute myeloid leukemia (AML) cells and stromal. It has been demonstrated that CD4 plays a critical role in AML development. However, studies of functional single nucleotide polymorphisms (SNPs) in CD44 gene have not touched upon AML. This case-control study probed the contribution of functional SNPs in CD44 gene to AML susceptibility in eastern Chinese population. Five representative SNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were opted and genotyped in 421 AML patients and 461 healthy subjects and the association with risk of AML was estimated by logistic regression. Moreover, the potential role of rs13347C > T in AML was further explored. Compared with the rs13347CC genotype, CT carriers had a significant increase in AML susceptibility (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.32-2.34), TT carriers had a further increased risk of AML (OR = 2.67; 95% CI = 1.69-4.21). Furthermore, our transient transfection assay and Western blot results demonstrated that the presence of rs13347T allele led to more CD44 expression. Yet, there exists no significant difference in genotype frequencies of the other four sites between cases and controls. Above findings suggest that rs13347C>T in 3'UTR of CD44 may be a genetic modifier for developing AML.

Heterozygous genetic variations of FOXP3 in Xp11.23 elevate breast cancer risk in Chinese population via skewed X-chromosome inactivation.

FOXP3 (forkhead box P3: also known as IPEX, XPID) is not only a hallmark of immunosuppressive regulatory T cells (Tregs), but also an X-linked breast cancer suppressor gene expressed in tumor cells. A two-stage investigation was conducted in individuals from northern, southern and eastern China. Individuals carrying a FOXP3 rs2294021CT genotype showed about 1.5-fold increased risk of breast cancer compared with TT carriers. In a related biochemical assay, the rs2294021C allele was found to significantly enhance transcription activity, leading to higher mRNA levels of FOXP3 compared with T allele. Moreover, the number of Tregs and its corresponding interleukin-10 (IL-10) secretion were elevated whereas the proliferation of antitumor T cells was decreased in the C-allele carriers. The breast cancer oncogenes Her-2/ErbB2 and Skp2 were also found to be significantly inhibited in C-allele carriers. Moreover, skewed X-chromosome inactivation (SXCI) analysis showed that rs2294021CT carriers with SXCI showed higher risk than the homozygous carriers and CT carriers without SXCI, suggesting a possible interaction between the rs2294021CT genotype and SXCI. Taken together, these findings indicate that the rs2294021CT genotype may increase an individual's susceptibility to breast cancer by breaking the balance between Treg-mediated immune tolerance and FOXP3-controlled tumor-suppressive effect.

A genetic polymorphism in lincRNA-uc003opf.1 is associated with susceptibility to esophageal squamous cell carcinoma in Chinese populations.

The development of esophageal squamous cell carcinoma (ESCC) is a multifactorial process, and associations between genetic variants and ESCC have been identified in genome-wide association studies. The aim of this study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on ESCC susceptibility in Chinese populations. We scoured exons of lincRNAs located in ESCC susceptibility loci for all probable functional SNPs. These 52 SNPs were opted for and genotyped in 1493 ESCC patients and 1553 cancer-free controls from eastern and southern Chinese populations, and their associations with the risk for ESCC were estimated using logistic regression. Functional relevance was further examined by biochemical assays. Significant differences were found between patients and controls in the genotype frequencies for the rs11752942A>G site in the lincRNA-uc003opf.1 exon. Compared with the rs11752942AA genotype, AG and GG genotypes had a significantly reduced risk of ESCC (adjusted odds ratio = 0.73; 95% confidence interval = 0.63-0.84). Biochemical analysis demonstrated that, when compared with the A allele, the rs11752942G allele could markedly attenuate the level of lincRNA-uc003opf.1 both in vivo and in vitro by binding micro-RNA-149*, thereby affecting cell proliferation and tumor growth. These findings indicated that functional polymorphism rs11752942A>G in lincRNA-uc003opf.1 exon might be a genetic modifier for the development of ESCC.

IL-21 gene polymorphism is associated with the prognosis of breast cancer in Chinese populations.

Interleukin (IL)-21, which is secreted by activated CD4(+) T cells and NKT cells, has been found to be able to influence the humoral and cell-mediated immune responses and have potent antitumor activity in animal models. This study was to investigate the impact of genetic polymorphisms in IL-21 on survival of breast cancer. Four TagSNPs of IL-21 (rs12508721C>T, rs907715G>A, rs13143866G>A, rs2221903A>G) were selected and then genotyped in 891 patients with breast cancer in Eastern and Southern Chinese populations. We then examined the associations between these SNPs and overall survival. Potential function of rs12508721C>T and association between this variation and breast cancer prognosis were further studied. Overall, 121 of the patients had died over the followed-up period of 5 years. The IL-21 rs12508721T allele predicted longer five-year survival (HR = 0.347, 95 % CI = 0.187-0.644, P < 0.0001) in the discovery cohort, the independent validation cohort (HR = 0.429, 95 % CI = 0.244-0.755, P = 0.012), and combined group (HR = 0.447, 95 % CI = 0.301-0.667, P < 0.0001). Furthermore, our luciferase assay revealed that rs12508721T variant allele had a higher transcription activity and the RT-PCR and ELISA assay showed that rs12508721 variant genotypes (CT and TT) carriers have more IL-21 expression than CC carriers (P < 0.05). Our present study established a robust association between the functional polymorphism (rs12508721C>T) in IL-21 and prognosis of breast cancer, indicating that this polymorphism may be a potential biomarker for prognosis of breast cancer.

Functional polymorphisms in PIN1 promoter and esophageal carcinoma susceptibility in Chinese population.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which regulates the conformation of Pro-directed phosphorylation sites, has been identified as a critical catalyst involved in multiple oncogenic signaling pathways. Recently, it has been demonstrated that several putative functional polymorphisms of PIN1 gene were associated with cancer risk. This study examined whether genetic polymorphisms in promoter of PIN1 are associated with esophageal carcinoma susceptibility. Two common polymorphisms in PIN1, rs2233678 (-842G>C) and rs2233679 (-667C>T) were genotyped in this hospital-based case-control study of 699 esophageal carcinoma patients and 729 healthy controls. The results revealed that compared with the most common -842GG genotype carriers, the carriers of -842C variant genotypes (GC+CC) had significantly decreased risk of esophageal carcinoma [odds ratio (OR) = 0.55, 95 % CI = (0.40-0.75), P = 0.001]. No association was observed between the -667C>T polymorphism and the risk of esophageal carcinoma. Furthermore, we found that the haplotype of 'C(-842)-C(-667)' had a greater protected effect [OR = 0.67, 95 % CI = (0.47-0.96), P = 0.021]. Functional assay revealed that -842C variant genotypes (GC+CC) carriers had a lower transcription activity and mRNA expression level than the -842GG carriers. These results indicated that -842G>C genetic variant in PIN1 promoter may decrease the promoter activity, resulting in changes in the levels of PIN1 and modifying cancer susceptibility.

NBS1 rs1805794G>C polymorphism is associated with decreased risk of acute myeloid leukemia in a Chinese population.

As a key encoding protein gene of MRN (MRE11-RAD50-NBS1) complex, NBS1 plays a crucial role in maintaining genomic stability and preventing cell apoptosis, inflammation and tumorgenesis. Single nucleotide polymorphisms (rs2735383 and rs1805794) in NBS1 have been frequently studied in some cancers with discordant results in previous case-control studies. However, the relationship between these two functional polymorphisms and the susceptibility to acute myeloid leukemia (AML) in Chinese population has not been investigated. We performed a case-control study with 428 patients and 600 controls to detect the association between the two polymorphisms of NBS1 and the risk of AML in a Chinese population. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was carried out to determine the genotypes of potential functional SNPs in NBS1 gene. The results showed that compared with the homozygous carriers rs1805794CC, rs1805794GC genotype was significantly associated with decreased risk of AML in total subjects (adjusted odds ratio (OR) = 0.50; 95% CI = 0.37-0.67), the risk decreased even further in those carrying rs1805794GG genotype (OR = 0.23; 95% CI = 0.16-0.34). No significant association was found between rs2735383C>G polymorphism and the risk of AML (OR = 0.93; 95% CI = 0.71-1.22 for GC; OR = 0.78; 95% CI = 0.53-1.13 for CC, P = 0.152). These findings indicated that rs1805794G/C polymorphism in NBS1 may play a protective role in mediating the risk of AML.

Computationally-driven epitope identification of PEDV N-protein and its application in development of immunoassay for PEDV detection.

The nucleocapsid (N) protein is a suitable candidate for early diagnosis of porcine epidemic diarrhea virus (PEDV). Here, we identified the linear B-cell epitopes of the PEDV N-protein by integrating a computational-experimental framework and constructed three-dimensional (3D) structure model of the N protein using the ColabFold program in Google Colaboratory. Furthermore, we prepared the monoclonal antibodies against the predicted epitopes and recombinant N protein, respectively, and selected pairing mAbs (named 9C4 and 3C5) to develop a double-antibody sandwich immunochromatographic test strip using CdSe/ZnS quantum dots (QDs)-labelled 9C4 and 3C5 as capture and detection antibodies, respectively. This strip can specifically detect PEDV within 10 min with a detection limit of less than 6.25 × 103 TCID50/mL. In comparison with RT-PCR for testing 90 clinical samples, the relative sensitivity and specificity of the strip were found to be 98.0% and 100%, respectively, with a concordance rate of 98.9% and a kappa value of 0.978, indicating that QDs-ICTS is a reliable method for the application of PEDV detection in clinical samples.

Functional genetic variations in the IL-23 receptor gene are associated with risk of breast, lung and nasopharyngeal cancer in Chinese populations.

Interleukin-23 receptor (IL-23R) is a key element in the T-helper 17 cell-mediated inflammatory process, which plays an important role in the pathogenesis of cancer. In this study, we examined whether genetic polymorphisms in IL-23R are associated with cancer risk in 4936 cancer patients and 5664 control subjects from eastern and southern Chinese populations. We found that the C allele of the rs10889677A>C polymorphism in the 3'-untranslated region of IL-23R was inversely associated with risk of multiple types of cancer, including breast cancer, lung cancer and nasopharyngeal carcinoma. Healthy controls who harbored the rs10889677C allele had significantly decreased cancer risk (odds ratio = 0.74, 95% confidence interval = 0.71-0.78) compared with those who harbored the rs10889677A allele. Biochemical analysis demonstrated that the rs10889677A allele disrupted the binding site for the microRNA miR-let-7f, thereby increasing the transcription of the IL-23R in vitro and in vivo. Furthermore, cancer-free individuals carrying the rs10889677CC homozygous genotype had a lower proportion of regulatory T cells (Tregs) and a higher T-cell proliferation rate upon stimulation with concanavalin A than individuals carrying the rs10889677AA homozygous genotype. Our findings indicate that the IL-23R rs10889677A>C polymorphism may influence T-cell proliferation, resulting in changes in the levels of Tregs in vivo and modifying cancer susceptibility.

CD44 rs13347 C>T polymorphism predicts breast cancer risk and prognosis in Chinese populations.

INTRODUCTION: It has been demonstrated that the interplay of adhesion molecule CD44 and its ligands can regulate cancer cell proliferation, migration and invasion, as well as tumor-associated angiogenesis and is related to breast cancer patient survival. In this two-stage, case control study, we determined whether common functional tagSNPs (single nucleotide polymorphisms) are associated with breast cancer risk and prognosis. METHODS: Five tagSNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were selected and genotyped in 1,853 breast cancer patients and 1,992 healthy control subjects in Eastern and Southern populations. Potential function of rs13347C>T and association between this variation and breast cancer were further studied. RESULTS: Compared with the most common rs13347CC genotype, variant genotypes (CT and TT) increased an individual's susceptibility to breast cancer, especially in estrogen receptor (ER) negative patients (odds ratio (OR) = 1.37, 95%CI = 1.17 to 1.59 for ER positive patients; OR = 2.37, 95% CI = 2.00 to 2.80 for ER negative patients). We also found that rs13347CT+ TT genotypes predicts lower five-year survival rate (hazard ratio (HR) = 1.85, 95% CI = 1.09 to 3.15, P = 0.023), with the lowest survival probability in ER negative T allele carriers. Furthermore, our reporter assay findings, although preliminary and rather modest, showed that miR-509-3p may suppress CD44 expression more strongly in C allele carriers than T allele carriers (P < 0.01). Similarly, rs13347 variant genotypes (CT and TT) carriers were shown to have more CD44 expression than CC carriers in both immunohistochemistry (P < 0.001) and western blotting (P = 0.001) results. CONCLUSION: These findings suggest that CD44 rs13347C>T polymorphism may affect breast cancer development and prognosis by increasing CD44 expression.

The protective role of polymorphism MKK4-1304 T>G in nasopharyngeal carcinoma is modulated by Epstein-Barr virus' infection status.

MKK4 is a candidate tumor suppressor, which acts as a critical mediator of Epstein-Barr Virus (EBV)-induced c-Jun N-terminal kinase (JNK) activation. Functional polymorphism MKK4 -1304T>G has been showed to be protective in colorectal cancer or lung cancer. We hypothesized that genetic variants in the MKK4 promoter were associated with the risk of nasopharyngeal carcinoma (NPC). Two common polymorphisms in MKK4, -1304T>G and -1044A>T were genotyped in two independent case-control panels of Eastern and Southern Chinese populations, totally containing 1237 NPC and 1328 controls. We found that compared to the most common -1304TT genotype, carriers of variant genotypes (-1304TG+GG) were associated with a significantly reduced risk for NPC in total subjects (adjusted OR = 0.78; 95%CI = 0.67-0.94). Further stratification analysis showed that the protective effect was more pronounced in EBV negative status (adjusted OR = 0.51; 95%CI = 0.41-0.68) but restrained in those with EBV infection (adjusted OR = 1.05; 95%CI = 0.88-1.26), and that the -1304GG variant genotypes interacted with EBV negative status on reducing cancer risk (p = 0.011). However, no significant association was observed between the -1044A>T polymorphism and risk of NPC. Our data suggest that the protective role of genetic variant MKK4 -1304T>G is restrained in NPC with EBV infection. These findings implicate the role of EBV and MKK4 -1304 T>G interaction as a causative factor for the NPC.

Functional polymorphism in the EpCAM gene is associated with occurrence and advanced disease status of cervical cancer in Chinese population.

The epithelial cell adhesion molecule (EpCAM) was originally identified as a tumor associated antigen, attributable to its high expression on rapidly proliferating tumors of epithelial origin. EpCAM plays vital roles in carcinogenesis, tumor progression and metastasis in most tumors. A non-synonymous polymorphism (rs1126497 C/T) was found in exon 3 of EpCAM, which cause a transition from 115 Met to 115 Thr. Another polymorphism (rs1421 A/G) in the 3'UTR causes loss of has-miR-1183 binding. We performed a multiple independent case-control analysis to assess the association between EpCAM genotypes and cervical cancer risk. Genotyping a total of 518 patients with cervical cancer and 723 control subjects in a Chinese population, we observed that the variant EpCAM genotypes (rs1126497 CT, and TT) were associated with substantially increased risk of cervical cancer. Compared with the rs1126497 CC genotype, CT genotype had a significantly increased risk of cervical cancer (Crude OR = 1.70; 95% CI = 1.33-2.20; adjusted OR = 1.72; 95% CI = 1.33-2.22), the TT carriers had a further increased risk of cervical cancer (Crude OR = 1.94; 95% CI = 1.01-3.72; adjusted OR = 1.96; 95%CI = 1.01-3.81), and there was a trend for an allele dose effect on risk of cervical cancer (P < 0.001). Moreover, the allele T increases the risk for invasive disease or metastatic disease, compared with C allele. However, there exists no significant difference in genotype frequencies of rs1421 A/G site between cases and controls (P = 0.798). These findings suggest that rs1126497 C/T polymorphism in EpCAM may be a genetic modifier for developing cervical cancer.

A five-year review of prevalence and treatment outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis in the Henan Provincial Tuberculosis Clinical Medicine Research Centre.

OBJECTIVES: This study investigated the prevalence and significant clinical outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis (pre-XDR-plus) in Henan Provincial Chest Hospital between 2017 and 2021. METHODS: We analysed and summarized the drug sensitivity test (DST) results of clinical Mycobacterium tuberculosis (MTB) strains in TB patients seeking care in the Tuberculosis Clinical Medical Research Centre of Henan Province between 2017 and 2021. Medical records of pre-extensively drug-resistant plus additional drug-resistant TB patients were statistically analysed, including demographic characteristics, regimens, and outcomes. RESULTS: Of the 3689 Mycobacterium tuberculosis strains, 639 (17.32%), 353 (9.56%), and 109 (2.95%), multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (pre-XDR), and pre-XDR-plus, respectively. The proportion of MDR decreased from 19.1% in 2017 to 17.5% in 2021 (χ2 = 0.686, P = 0.407), the proportion of pre-XDR from 11.4% in 2017 to 9.0% in 2021 (χ2 = 2.39, P = 0.122), and pre-XDR-plus from 4.7% in 2017 to 1.8% in 2020, with the declining trend was significant (χ2 = 9.348, P = 0.002). The most commonly used anti-TB drugs were pyrazinamide (PZA, 37/46, 80.43%) and cycloserine (CS, 32/46, 69.57%), followed by linezolid (LZD, 25/46, 54.35%), protionamide (TH, 25/46, 54.35%), and para-aminosalicylic acid (PAS, 23/46, 50.00%). Patients receiving the LZD regimen were 5 times more likely to have a favourable outcome than those not receiving LZD (OR = 6.421, 95% CI 2.101-19.625, P = 0.001). Patients receiving a regimen containing CS were 4 times more likely to have a favourable outcome compared to those not taking CS (OR = 5.444, 95% CI 1.650-17.926, P = 0.005). CONCLUSIONS: Our data suggest that the population of pre-XDR-plus had significantly decreased over the past five years in the Henan Provincial Chest Hospital. The COVID-19 and flood disaster affect TB patients' selection of medical services. In addition, the pre-XDR-plus patients whose regimens contain LZD or CS were more likely to have favourable outcomes.

Functional variant (-1304T>G) in the MKK4 promoter is associated with decreased risk of acute myeloid leukemia in a southern Chinese population.

As a member of the MAPK kinase family, mitogen-activated protein kinase kinase (MKK) 4 (NM_003010.2) is know to be involved in the regulation of apoptosis, inflammation, and tumorigenesis. Several polymorphisms have been identified in the promoter region of the MKK4 gene and we hypothesized that genetic variations in this region may alter gene expression, and thus cancer risk. In the present study, we genotyped two polymorphisms in the promoter of the MKK4 gene, namely -1304T>G (rs3826392) and -1044A>T (rs3809728), in 433 patients with AML and 600 controls, and assessed the association between those polymorphisms and the risk of AML. Compared with the -1304TT genotype, patients with the -1304TG genotype had a significantly decreased risk of AML (adjusted odds ratio (OR) 0.67; 95% confidence interval (CI) 0.51-0.87), with the risk decreased even further in those carrying -1304GG (OR 0.56; 95% CI 0.31-0.97). Additional experiments, which focused on reporter gene expression driven by MKK4 promoters, demonstrated that the presence of a -1304G allele led to greater transcriptional activity than the presence of a -1304T allele. However, no significant association was observed between the MKK4-1044A>T polymorphism and the risk of AML. These findings suggest that the functional -1304G>T variant may contribute to the risk of AML by enhancing the transcriptional activity of MKK4. Thus, this polymorphism may be a genetic modifier for the development of AML.

Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma.

As a component of the MRN (MRE11/RAD50/NBS1) complex, NBS1 plays an important role in cellular response to DNA damage and the maintenance of chromosomal integrity. The NBS1 E185Q polymorphism (8360G>C, rs1805794) has been frequently studied in some cancers with discordant results, but its association with nasopharyngeal carcinoma (NPC) in Chinese population has not been investigated. Moreover, there is no report about the association between NBS1 3'UTR variant rs2735383 and the risk of NPC. A multiple center case-control analysis was performed to assess the association between NBS1 polymorphisms and NPC risk in Eastern and Southern Chinese population. The genotypes and haplotypes were determined in 1052 cases and 1168 controls and the associations with risk of NPC were estimated by logistic regression. Cell migration assays were performed in 24-well transwell chambers to detect the effects of NBS1 E185Q SNP on cell migration. We observed significant difference in genotype frequencies at the rs1805794 C/G site between cases and controls (P(trend) < 0.0001). The C allele increases the risk for invasive disease or metastatic disease, compared with G allele. More over, CNE-2 cells (NPC cell line) transfected with pcDNA-NBS1-185Q (8360CC) had significantly higher migration levels than those transfected with pcDNA-NBS1-185E (8360GG) (P = 0.024). These findings suggest that E185Q polymorphism in NBS1 may be a genetic modifier for the occurrence and aggression of NPC.

Functional genetic variations of cyclooxygenase-2 and susceptibility to acute myeloid leukemia in a Chinese population.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the synthesis of prostaglandins, which are known to play important roles in the proliferation and differentiation of leukemia cells, and inhibitors of COX-2 can suppress the proliferation and differentiation of human leukemia cell lines. Single-nucleotide polymorphisms (-765G/C: rs20417, -1195A/G: rs689466, and -1290A/G: rs689465) in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. METHODS: In this case-control study, the genotypes of potential functional Single-nucleotide polymorphisms in COX-2 gene were determined with PCR-RFLP method in 446 patients and 725 controls. COX-2 mRNA level in Acute myeloid leukemia (AML) bone marrow and COX-2 protein level in serum samples were examined by real-time PCR and ELISA, respectively. RESULTS: It was found that carriers with -765CC genotypes had a 2.19-fold (95% CI = 1.24-3.88; P < 0.001) excess risk of developing AML compared with non-carriers. A greater risk of developing AML was observed for A(-1195) -C(-765) haplotype compared with G(-1195) -G(-765) haplotype. Moreover, individuals with -765C-containing genotypes had significantly increased COX-2 mRNA level and protein level compared with the -765G-containing counterparts. CONCLUSIONS: These findings indicate that -765G/C polymorphism in COX-2 may play a vital role in mediating individual susceptibility to AML.

A sequence polymorphism in miR-608 predicts recurrence after radiotherapy for nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is treated with radiotherapy and other modalities, but there is little information on individual genetic factors to help predict and improve patient outcomes. Single-nucleotide polymorphisms (SNP) in mature microRNA (miRNA) sequences have the potential to exert broad impact as miRNAs target many mRNAs. The aim of this study was to evaluate the effects of SNPs in mature miRNA sequences on clinical outcome in patients with nasopharyngeal carcinoma receiving radiotherapy. In particular, we analyzed associations between seven SNPs and nasopharyngeal carcinoma locoregional recurrence (LRR) in 837 patients from eastern China, validating the findings in an additional 828 patients from southern China. We found that miR-608 rs4919510C > G exhibited a consistent association with LRR in the discovery set [HR, 2.05; 95% confidence interval (CI), 1.35-3.21], the validation set (HR, 2.24; 95% CI, 1.45-3.38), and the combined dataset (HR, 2.08; 95% CI, 1.41-3.26). Biochemical investigations showed that rs4919510C > G affects expression of miR-608 target genes along with nasopharyngeal carcinoma cell growth after irradiation in vivo and in vitro. Notably, X-ray radiation induced more chromatid breaks in lymphocyte cells from rs4919510CC carriers than in those from subjects with other genotypes (P = 0.0024). Our findings reveal rs4919510C > G in miR-608 as a simple marker to predict LRR in patients with radiotherapy-treated nasopharyngeal carcinoma.

Association between the p73 exon 2 G4C14-to-A4T14 polymorphism and cancer risk: a meta-analysis.

The TP53 homolog p73 is structurally and functionally similar to TP53 and plays an important role in modulating cell-cycle control, apoptosis, and cell growth. G4C14-to-A4T14 is the most commonly studied polymorphism of this gene for its association with risk of cancers, but the results are confusing rather than conclusive. We performed a meta-analysis using 21 eligible studies with a total of 7581 patients and 10,413 controls to summarize the data for an association between the p73 G4C14-to-A4T14 polymorphism and cancer risk. Compared with the common GC/GC genotype, the AT carriers (AT/GC, AT/AT) had a 1.18-fold elevated risk of cancer (95% confidence interval [CI]=1.11-1.25, p<0.00001) in a dominant genetic model as estimated in a fixed effect model. The effect of the G4C14-to-A4T14 polymorphism was further evaluated through stratification analysis. In four lung cancer studies, the variant genotypes had a significantly increased risk of lung cancer (odds ratio [OR]=1.16, 95% CI=1.04-1.28, p=0.005). Similar phenomena were also found in two squamous cell carcinoma of the head and neck studies (OR=1.32, 95% CI=1.12-1.56, p=0.0010), two oral cancer studies (OR=1.57, 95% CI=1.26-1.95, p<0.0001), and three colorectal cancer studies (OR=1.23, 95% CI=1.01-1.50, p=0.04). Increased risk of cancer associated with G4C14-to-A4T14 variant genotypes was pronounced in Caucasians (OR=1.21, 95% CI=1.11-1.31, p<0.00001), the Japanese population (OR=1.24, 95% CI=1.01-1.52, p=0.04), and the Korean population (OR=1.27, 95% CI=1.07-1.52, p=0.007). Our meta-analysis suggests that the p73 G4C14-to-A4T14 polymorphism genotypes (GC/AT+AT/AT) may be associated with an increased risk of cancer in most cancer types and ethnicities.

The association between -1304T>G polymorphism in the promoter of mitogen-activated protein kinase kinase 4 gene and the risk of cervical cancer in Chinese population.

Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations, and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its functions and thus cancer risk. In the current, hospital-based case-control study of 471 cervical cancer cases and 600 sex and age frequency-matched cancer-free controls in an Eastern Chinese population, we genotyped two common polymorphisms in the MKK4 promoter region (-1304T>G, rs3826392 and -1044A>T, rs3809728)c and assessed their associations with the risk of cervical cancer. We found that compared with the most common -1304TT genotype, carriers of -1304G variant genotypes had a significantly decreased risk of cervical cancer [odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.53-0.92 for TG, and OR = 0.52; 95%CI = 0.30-0.91 for GG] in an allele dose-response manner (adjusted P(trend) = 0.004). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 mRNA expression levels of the G variant carriers was significantly higher in tumor tissues than those of the -1304TT genotype. However, no significant association was observed between the -1044A>T polymorphism and risk of cervical cancer. Our data suggest that the functional -1304G variant in the MKK4 promoter contributes to a decreased risk of cervical cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to cervical cancer.

Genetic variations in CD14 promoter and acute lymphoblastic leukemia susceptibility in a Chinese population.

Recent findings suggest that CD14 may play a role in tumor development. Previous case-control studies have revealed that CD14 -260C/T and -651 C/T polymorphisms contribute to the risk of human diseases. However, the relationship between these two functional polymorphisms and susceptibility to acute lymphoblastic leukemia (ALL) has not been explored. In this study, we performed a case-control study in a Chinese population. We found that an increased risk of ALL was associated with the -260 TT (odds ratio [OR]=1.85, 95% confidence interval [CI]=1.26-2.63) genotype compared with the CT or CC genotype. No significant association was found between -651 CC genotype and ALL (OR=1.13, 95% CI=0.77-1.69). Moreover, the increased risk was only associated with the -260 TT genotype in B-ALL (OR=1.99, 95% CI=1.34-3.01) but not in T-ALL (OR=1.48, 95% CI=0.79-2.84). The findings suggest that CD14-260C/T polymorphism can contribute to B-ALL risk in a Chinese population.