Identification of a RAD51B enhancer variant for susceptibility and progression to glioma.

BACKGROUND: RAD51B plays a significant role in homologous recombination-mediated repair of DNA double-strand breaks. Many enhancer variants are involved in cancer development and progression. However, the significance of enhancer variants of RAD51B in glioma susceptibility and progression remains unclear. METHODS: A case-control study consisting of 1056 individuals was conducted to evaluate the associations of enhancer variants of RAD51B with glioma susceptibility and progression. Sequenom MassARRAY technology was used for genotyping. The function of enhancer variants was explored by biochemical assays. RESULTS: A significantly decreased risk of glioma was associated with rs6573816 GC genotype compared with rs6573816 GG genotype (OR = 0.66, 95% CI 0.45-0.97; P = 0.034). Multivariable Cox regression revealed that rs6573816 was significantly associated with glioma progression in a sex-dependent manner. Worse PFS was found in the male patients with high grade glioma carrying rs6573816 GC or CC genotype (HR = 2.28, 95% CI 1.14-4.57; P = 0.020). The rs6573816 C allele repressed enhancer activity by affecting transcription factor POU2F1 binding, which resulted in lower expression of RAD51B. Remarkably attenuated expression of RAD51B was observed following POU2F1 knockdown. Consistently, positive correlation between the expression of POU2F1 and RAD51B was found in lymphoblastic cells and glioma tissues. CONCLUSIONS: These results indicate that an enhancer variant of RAD51B rs6573816 influences enhancer activity by changing a POU2F1 binding site and confers susceptibility and progression to glioma.

Sex-specific disparities of serum pepsinogen I in relation to body mass index.

OBJECTIVES: The clinical significance of serum pepsinogen (PG) for screening gastric cancer has been a controversial topic. Serum PG I levels have been demonstrated to be correlated with age, sex, and the Helicobacter pylori (HP) infection. However, the underlying factors that influence serum PG I variations remain to be fully elucidated. We aimed to evaluate the impacts of sex and body mass index (BMI) on PG I in Chinese population. METHODS: The cross-sectional study recruited 4,299 apparently healthy participants in Fujian Province. Serum PG levels were automatically measured using ELISA method. Serum H. pylori-IgG antibody was detected by the colloidal gold immunoassay. Clinical characteristics were obtained by questionnaire. RESULTS: Totally, 2,263 participants who had tests of serum PG and anti-HP IgG antibody were enrolled. Increased BMI and serum uric acid were observed in males with low PG I value (<70 µg/L). Multiple logistic regression showed the presence of overweight was the independent risk factor for male participants with low PG I level (odds ratio [OR] 1.519; p=0.017). However, the association was not found in females. CONCLUSIONS: Sex-specific association of serum low PG I with overweight was observed in the southeast coastal areas of China. Thus, effects of sexual dimorphism should not be ignored during the clinical utilization of serum PG I.

Serum microRNA-4297 is a sex-specific predictive biomarker of glioma grade and prognosis.

Background: Gliomas account for nearly 80% of brain cancers, tending to occur more frequently in men with adverse outcomes. Emerging microRNAs have been positioned as promising predictors for glioma's histological grade and prognosis. However, there have been few studies concerning the sex-biased impacts on the clinical approach for the potential microRNA-4297 (miR-4297). Methods: We utilized GSE139031micro-RNAs profiling to analyze serum miR-4297 expression in glioma. A total of 114 newly diagnosed glioma patients at the First Affiliated Hospital of Fujian Medical University from January 2017 to February 2021 were recruited and prospectively followed up. The association of miR-4297 levels with glioma grade and prognosis was investigated. Luciferase reporter gene assays and genotype analyses were carried out to explore the potential mechanism of sexually dimorphic miR-4297 in glioma. Results: Serum miR-4297 levels were notably down-regulated in glioma. Besides, serum miR-4297 levels were positively associated with the high grades, which were exclusively present for females. The positive correlations of miR-4297 with O6-methylguanine-DNA methyltransferase (MGMT) protein and mean platelet volume were also observed in females. IDH-mutant females had decreased miR-4297. Median PFS time for females with miR-4297 ≥ 1.392 was distinctly shorter than those with miR-4297 <1.392 (12.3 months vs. 42.89 months, p = 0.0289). Based on multivariate logistic regression, miR-4297-based equation model was established as FHGRS. AU-ROC analysis revealed FHGRS exhibited a robust performance in predicting high-grade glioma in females (p < 0.001), whereas there was no such relationship in males. Furthermore, the MGMT-3'UTR variant rs7896488 in the specific binding region of miR-4297 was correlated with prognosis. Conclusion: Our study uncovers sex-dependent characterization of serum miR-4297 in predicting glioma grade and the relapse risk for female patients, which underscores the clinical benefits of sex-specific analysis in non-coding RNA research.

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated. METHODS: The associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case-control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown. RESULTS: We found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39-0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40-0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27-0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35-0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21-0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population. CONCLUSIONS: The study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site.

Argon-Helium Cryoablation for Cutaneous Squamous Cell Carcinoma in the Elderly.

Cutaneous squamous cell carcinoma (cSCC) is a common type of malignant neoplasm in non-melanoma skin cancer (NMSC). Most cases of simple cSCC are considered curable by surgical removal of the lesion. However, clinical treatments for cSCC with medium- or large-sized lesions are difficult. Meanwhile, the effectiveness of the treatments is not guaranteed, especially for elderly patients, because of an intolerance to surgical resection or other adjuvant modalities. In such cases, safe and effective treatments with excellent aesthetic outcomes are urgently needed. In this study, we reported 6 elderly cSCC patients with medium- or large-sized lesions treated with argon-helium cryoablation. The average age of all 6 patients was 78 years (range 72-85 years). They were all diagnosed with cSCC with a median tumor size of 5.8 cm (range 2.5-15.5 cm) and dermal invasion. Complete ablation was achieved in all cases after a single ablation session (2 freeze-thaw cycles). Patients experienced mild pain and hemorrhage after ablation, but the symptoms were manageable. One patient developed infection and fever because of extensive necrosis of the tumor, which was eventually cured after treatment. All patients obtained good cosmetic outcomes, and their quality of life improved significantly. In the 5-year follow-up study, 4 patients were alive while 2 patients died of unrelated diseases 3 years after cryotherapy. None of the 6 patients had a recurrence. These results suggested the feasibility of argon-helium cryoablation as a novel therapeutic strategy for elderly cSCC with medium- or large-sized lesions.

Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant.

Mitogen-activated protein kinase-associated protein 1 (MAPKAP1) is a unique component of the mechanistic target of rapamycin (MTOR) pathway which plays a pivotal role in carcinogenesis. The role of enhancer variant in carcinogenesis receives increased attentions. However, the significance of enhancer variants of MAPKAP1 in glioma has not yet been investigated. The associations of enhancer variants of MAPKAP1 with glioma susceptibility were evaluated in a cohort of 400 glioma patients and 651 controls. The function of glioma susceptibility locus was examined by a set of biochemical assays. We found that an enhancer variant of MAPKAP1 rs473426 was associated with a significantly increased risk of glioma in a dominant manner (OR 1.53, 95% CI 1.13-2.06; P = 0.006). The association for rs1339499 located in the same enhancer approached the borderline of significance after multiple testing correction (OR 0.74, 95% CI 0.56-0.98; P = 0.037). Furthermore, cumulative associations of rs473426 and rs1339499 with glioma risk were observed (P = 0.011). Functional analyses showed that the risk allele rs473426 C downregulated the regulatory activity of enhancer by reducing the binding affinity of a transcriptional activator NFΙC, which resulted in lower gene expression both in vitro and in vivo. These results demonstrate for the first time that enhancer variant of MAPKAP1 confers susceptibility to glioma by downregulation of MAPKAP1 expression, and provide further evidence highlighting MAPKAP1 as a cancer suppressor in glioma carcinogenesis.

An intronic genetic variation of MGMT affects enhancer activity and is associated with glioma susceptibility.

PURPOSE: O6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in repairing damaged DNA caused by alkylating agents. A number of cancer susceptibility loci have been recognized as enhancer variants. This study aimed to explore the significance of enhancer variants of MGMT in glioma susceptibility. PATIENTS AND METHODS: A retrospective case-control study consisting of 150 glioma patients and 327 controls was conducted to test whether enhancer variants of MGMT are associated with glioma susceptibility. Genotypes were determined by Sequenom MassARRAY technology. Associations were estimated by logistic regression. Biochemical assays were used to examine the function of glioma susceptibility locus. RESULTS: We found that the A allele of rs10764901, an intronic variant of MGMT, was associated with a significantly decreased risk of glioma. The rs10764901 AA genotype carriers had an OR of 0.49 (95% CI, 0.24-0.98; P=0.045) compared with the rs10764901 GG genotype. When the rs10764901 AG and AA genotypes were pooled for analysis, a significantly decreased risk of glioma was also found (OR, 0.63; 95% CI, 0.43-0.93; P=0.021). Functional analyses showed that the rs10764901 A allele drove a lower luciferase expression and had higher transcription factor binding affinity than the G allele. CONCLUSION: An enhancer variant of MGMT rs10764901 affects the regulatory activity of enhancer by altering the binding affinity of transcription factors and is associated with glioma susceptibility.

Identification of expression quantitative trait loci of MTOR associated with the progression of glioma.

Mechanistic target of rapamycin (MTOR) encodes a key modulator of cell growth, proliferation, and apoptosis. Previous studies have demonstrated that the dysregulation of MTOR is involved in the development and progression of several types of cancer, including glioma. In the present study, a comprehensive analysis was conducted to examine whether the expression quantitative trait loci (eQTLs) of MTOR are associated with the progression of glioma. Candidate eQTLs of MTOR were obtained from the Genotype-Tissue Expression eQTL Browser. The Kaplan-Meier method and multivariate Cox model were used to analyze the progression-free survival time of glioma patients. Based on the analysis of 138 glioma patients, one eQTL of MTOR, rs4845964, was demonstrated to be significantly associated with the progression of glioma in a dominant manner. The adjusted hazard ratios (HRs) for patients with the AG or AA genotype at rs4845964 were 2.82 [95% confidence interval (CI), 1.27-6.27; P=0.0111] and 2.79 (95% CI, 1.10-7.07; P=0.0312), respectively, compared with those with the GG genotype. When the rs4845964 AG and AA genotypes were combined for analysis, the HR was 2.70 (95% CI, 1.25-5.82; P=0.0114) vs. the GG genotype. Stratified analyses revealed similar associations between the rs4845964 genotypes and the progression of glioma in all subgroups (following stratification by age, sex and tumor grade). These results demonstrate for the first time that the MTOR eQTL rs4845964 is associated with the progression of glioma.

Sex-dependent association of preoperative hematologic markers with glioma grade and progression.

Neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte ratio, the systemic immune-inflammation index (SII), and red blood cell distribution width (RDW), have been recognized as promising predictors for histological grade and prognosis in multiple cancer types. However, few investigations illustrated the impacts of sex on the clinical utility of hematologic markers. Patients with primary gliomas were retrospectively reviewed. The association between grade and inflammatory markers by sex were investigated by univariate and multivariate analysis. The discrimination ability of logistic regression model was evaluated by the area under the receiver-operating characteristic curve (AUC) for high-grade glioma (HGG). Kaplan-Meier progressionfree survival (PFS) curves were plotted to assess the prognostic value of RDW. In subgroup analysis, distinctively elevated NLR and SII levels were exclusively present in male HGGs group (p = 0.001); whereas RDW notably increased in female HGGs group (p = 0.001). On multivariate analysis, increased odds ratio of HGGs was exclusively observed for female patients with elevated RDW (odds ratio = 1.589). Moreover, regression model developed by RDW exhibited an excellent discriminative ability for the prediction of HGGs in female patients (AUC = 0.817). Median progression time with RDW < 13.2 versus RDW ≥ 13.2 was 62.5 versus 33.0 months (log rank p = 0.017). Older females (≥ 45 years) with increased RDW levels portended worse survival (HR 3.693, 95% CI 1.747-8.325, p = 0.001). Meanwhile, the significant association of RDW levels with PFS in male subgroup was not observed (p > 0.05). In conclusion, superior to NLR and SII, RDW would be sex-specific predictor for tumor grade and progression for HGG female patients.

Identification of expression quantitative trait loci of RPTOR for susceptibility to glioma.

Expression quantitative trait loci (eQTLs) have been recognized to be more likely to associate with complex diseases including cancer. As an essential scaffold for MTOR complex 1, RPTOR is necessary for the MTOR-catalyzed phosphorylation. This study examined the associations between the eQTLs of RPTOR and glioma susceptibility. The eQTLs of RPTOR were obtained from GTEx eQTL Browser. Associations were estimated by logistic regression models. On the basis of analysis of 138 cases with glioma and 327 cancer-free population controls, we demonstrated that the eQTL of RPTOR, rs7502563, was significantly associated with a decreased glioma risk [odds ratio (OR) = 0.59, 95 % confidence interval (CI) = 0.38-0.89, P = 0.0123] in a dominant manner. Stratified analyses indicated that the association between rs7502563 and glioma was more pronounced in females (OR = 0.40, 95 % CI = 0.20-0.80, P = 0.0091), older subjects (OR = 0.47, 95 % CI = 0.26-0.86, P = 0.0135), and subjects with high-grade glioma (OR = 0.45, 95 % CI = 0.27-0.77, P = 0.0031). Moreover, an interest gradual decrease in OR with higher grade glioma was observed. Further analysis of the extracted data from GTEx eQTL Browser found that rs7502563 G allele was associated with significantly higher expression of RPTOR in all HapMap populations. Our results demonstrate for the first time that the eQTL of RPTOR, rs7502563, is susceptible to glioma.

Red blood cell distribution width levels correlate with liver fibrosis and inflammation: a noninvasive serum marker panel to predict the severity of fibrosis and inflammation in patients with hepatitis B.

We aimed to study whether red blood cell distribution width (RDW) could be one of the variables determining the extent of liver fibrosis and inflammation in patients with biopsy-proven hepatitis B. A total of 446 hepatitis B virus-infected patients who underwent liver biopsy were divided into 2 groups: absent or mild and moderate-severe according to the severity of liver fibrosis and inflammation. The independent variables that determine the severity of liver fibrosis and inflammation were explored. RDW values increased with progressive liver fibrosis and inflammation. After adjustments for other potent predictors, liver fibrosis (moderate-severe) was independently associated with RDW, platelet, and albumin (odds ratio = 1.121, 0.987, and 0.941, respectively), whereas increased odds ratios of significant inflammation were found for RDW, alanine aminotransferase, albumin, and PLT (odds ratio = 1.146, 1.003, 0.927, and 0.990, respectively). The sensitivity and specificity of model A were 70.0% and 62.9% for detection of significant liver fibrosis [area under the receiver-operating characteristic curve (AUC) = 0.713, P < 0.001]. The sensitivity and specificity of model B were 66.1% and 79.4% for predicting advanced liver inflammation (AUC = 0.765, P < 0.001). Compared with preexisting indicators, model A achieved the highest AUC, whereas model B showed a higher AUC than RDW to platelet ratio (0.670, P < 0.001) and FIB-4 (0.740, P = 0.32). RDW may provide a useful clinical value for predicting liver fibrosis and necroinflammation in hepatitis B-infected patients with other markers.