Genetic variants reduced POPs-related colorectal cancer risk via altering miRNA binding affinity and m6A modification.

Exposure to persistent organic pollutants (POPs) may contribute to colorectal cancer risk, but the underlying mechanisms of crucial POPs exposure remain unclear. Hence, we systematically investigated the associations among POPs exposure, genetics and epigenetics and their effects on colorectal cancer. A case-control study was conducted in the Chinese population for detecting POPs levels. We measured the concentrations of 24 POPs in the plasma using gas chromatography-tandem mass spectrometry (GC-MS/MS) and evaluated the clinical significance of POPs by calculating the area under the receiver operating characteristic curve (AUC). To assess the associations between candidate genetic variants and colorectal cancer risk, unconditional logistic regression was used. Compared with healthy control individuals, individuals with colorectal cancer exhibited higher concentrations of the majority of POPs. Exposure to PCB153 was positively associated with colorectal cancer risk, and PCB153 demonstrated superior accuracy (AUC=0.72) for predicting colorectal cancer compared to other analytes. On PCB153-related genes, the rs67734009 C allele was significantly associated with reduced colorectal cancer risk and lower plasma levels of PCB153. Moreover, rs67734009 exhibited an expression quantitative trait locus (eQTL) effect on ESR1, of which the expression level was negatively related to PCB153 concentration. Mechanistically, the risk allele of rs67734009 increased ESR1 expression via miR-3492 binding and m6A modification. Collectively, this study sheds light on potential genetic and epigenetic mechanisms linking PCB153 exposure and colorectal cancer risk, thereby providing insight into the accurate protection against POPs exposure.

Genetic variants in C1GALT1 are associated with gastric cancer risk by influencing immune infiltration.

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-ß-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk (odds ratio, 0.83; 95% confidence interval [CI], 0.75-0.92; P = 3.95 × 10 -4). C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues, and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates (hazards ratio, 1.33; 95% CI, 1.05-1.68; P log-rank = 1.90 × 10 -2). Furthermore, we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4 + T cells and macrophages. These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.

Genetic variants in hypoxia-inducible factor pathway are associated with colorectal cancer risk and immune infiltration.

Hypoxia-inducible factor (HIF) pathway genes influence tumorigenesis and immune status. However, the associations between genetic variants in hypoxia-related genes and colorectal cancer risk and the immune status of hypoxia-associated genes in colorectal cancer have not been systematically characterized. The associations between genetic variants and colorectal cancer risk were evaluated in Chinese, Japanese and European populations using logistic regression analysis. The relationships between target genes and tumour immune infiltration were predicted by Tumour Immune Estimation Resource (TIMER). We found that rs34533650 in EPAS1 was associated with colorectal cancer risk (OR = 1.43, 95% CI = 1.20-1.70, P(FDR) = 8.35 × 10-4 ), and this finding was validated in two independent populations (Japanese: OR = 1.07, 95% CI = 1.01-1.15, p = 3.38 × 10-2 ; European: OR = 1.11, 95% CI = 1.03-1.19, p = 6.04 × 10-3 ). EPAS1-associated genes were enriched in immune-related pathways. In addition, we found that EPAS1 copy number variation (CNV) was associated with the degree of infiltration of immune cells and observed correlations between EPAS1 expression and immune cell infiltration levels in colorectal cancer. These results highlight that genetic variants of hypoxia-related genes play roles in colorectal cancer risk and provide new insight that EPAS1 might be a promising predictor of colorectal cancer susceptibility and immune status.

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk.

Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159-1.583, P = 1.33 × 10 -4; rs2683524: OR = 1.378, 95% CI: 1.164-1.632, P = 2.03 × 10 -4; rs11540872: OR = 1.472, 95% CI: 1.193-1.815, P = 3.06 × 10 -4). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer ( P trend = 2.87 × 10 -12). We found that PRR13, being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3' untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

Genetic Modulation of BET1L Confers Colorectal Cancer Susceptibility by Reducing miRNA Binding and m6A Modification.

Genetic variants in regions encoding 3' untranslated regions (UTR) of mRNA potentially alter miRNA binding affinity and N6-methyladenosine (m6A) levels to affect gene expression. A better understanding of the association of these variants with colorectal cancer susceptibility could facilitate development of cancer prevention and treatment approaches. Here, we analyzed miRNA expression profiles and integrated genetic analyses from 8,533 individuals to evaluate the effects of altered miRNA-binding sites on colorectal cancer risk. The single-nucleotide polymorphism rs11245997 in the BET1L 3'UTR was significantly associated with colorectal cancer risk. The rs11245997 A allele facilitated BET1L expression by disrupting miR-140-3p binding. It also reduced BET1L m6A modification, which upregulated BET1L expression levels through a mechanism mediated by the m6A methyltransferases (METTL14 and WTAP) and the m6A demethylase ALKBH5. Moreover, higher expression of BET1L was associated with advanced tumor stages and poor patient prognosis. Increased BET1L expression promoted growth of colorectal cancer cells in vitro and in vivo, which could be partially rescued with miR-140-3p overexpression. RNA sequencing and pathway analyses indicated that BET1L is associated with the steroid biosynthesis pathway through regulation of HSD17B7, CYP27B1, and COMT. These findings provide insights into the involvement of genetic variants of BET1L in the development and progression of colorectal cancer. SIGNIFICANCE: The integration of miRNA expression profiles and genetic variants identified rs11245997 as a colorectal cancer risk-related variant that reduces miR-140-3p binding and m6A modification, leading to BET1L upregulation to promote colorectal tumorigenesis.

Metal Exposure Promotes Colorectal Tumorigenesis via the Aberrant N6-Methyladenosine Modification of ATP13A3.

Element contamination, including that from heavy metals, is associated with gastrointestinal tumorigenesis, but the effects and mechanisms of crucial element exposure associated with colorectal cancer remain unclear. We profiled 56 elements by ICP-MS and used logistic regression, LASSO, BKMR, and GAM to identify colorectal cancer-relevant elements. A series of biochemical experiments were performed to demonstrate the cytotoxicity and the mechanisms of malignant transformation after metal exposure. Using an elementomics approach, we first found that the metal thallium (Tl) was positively correlated with many toxic metals and was associated with a significantly increased risk of colorectal cancer. Acute exposure to Tl induced cytotoxicity and cell death by accelerating the generation of reactive oxygen species and DNA damage. Chronic exposure to Tl led to the inhibition of cell death and thereby induced the malignant transformation of normal colon cells and xenograft tumor formation in nude mice. Furthermore, we describe the first identification of a significant metal quantitative trait locus for the novel colorectal cancer susceptibility locus rs1511625 near ATP13A3. Mechanistically, Tl increased the level of aberrant N6-methyladenosine (m6A) modification of ATP13A3 via the METLL3/METTL14/ALKBH5-ATP13A3 axis to promote colorectal tumorigenesis. This study provides a basis for the development of public health strategies for reducing metal exposure among populations at high risk for colorectal cancer.

Neutrophil extracellular traps induce a hypercoagulable state in glioma.

BACKGROUND: Venous thromboembolism (VTE) is one of the leading complications in glioma patients. Neutrophil extracellular traps (NETs) have been reported to play a critical role in the physiopathology of cancer. We aimed to investigate the presence and potential role of NETs in the hypercoagulable state in glioma patients. Moreover, we evaluated the interaction between NETs and endothelial cells (ECs) in glioma patients. METHODS: The plasma levels of NETs were detected by enzyme-linked immunosorbent assay. The NET procoagulant activity was performed based on fibrin formation assays. The NET generation and NET-treated ECs in vitro were observed by confocal microscopy. Activated platelets (PLTs) and PLT-neutrophil aggregates were detected by flow cytometry. RESULTS: Plasma NET markers were significantly higher in stage III/IV glioma patients than in stage I/II glioma patients and healthy subjects. PLTs from glioma patients tended to induce NET formation than those from healthy subjects. NETs contributed to the hypercoagulable state in glioma patients. After ECs were incubated with NETs isolated from stage III/IV glioma patients, they lost their intercellular connections and were converted into procoagulant phenotypes. Combining DNase I and activated protein C markedly decreased endothelial dysfunction. CONCLUSIONS: Our results showed the interaction between NETs and hypercoagulability in glioma patients. Targeting NETs may be a potential therapeutic and prevention direction for thrombotic complications in glioma patients.