Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy.

BACKGROUND: Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy. METHODS: The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort. RESULTS: Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P < 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P < 0.05). CONCLUSION: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.

CD39-Expressing CD8+ T Cells as a New Molecular Marker for Diagnosis and Prognosis of Esophageal Squamous Cell Carcinoma.

We aimed to explore the effect of CD39 expression on CD8+ T cells and on the diagnosis and prognosis of esophageal squamous cell carcinoma (ESCC). The independent prognostic factors for the surgical specimens of the 95 ESCC patients were screened by multivariate Cox regression analysis. Differential gene expression analysis was performed by the NetworkAnalyst platform based on data from the Gene Expression Omnibus (GEO). The expression of CD39 on CD8+ T cells in the CK+ region was higher in cancer tissue than in paracancerous tissue (p = 0.011), and high CD39-expressing CD8+ T cells in the CK+ region (HR, 2.587; p = 0.033) and high CD39-expressing CD8+ T cells in the CK- region (HR, 3.090; p = 0.008) were independent risk factors for prognosis in ESCC patients; the expression of ENTPD1 was upregulated in ESCC tissues compared to normal tissues (adjusted p < 0.001; log2 fold change = 1.99), and its expression was significantly positively correlated with the expression of PDCD1, CTLA4, and HAVCR2. High CD39-expressing CD8+ T cells can be used as a new molecular marker for the diagnosis and prognosis of ESCC, and the restoration of partially exhausted CD8+ T cells by inhibiting CD39 may be a new strategy for treating ESCC.

The Role of m6A Modification and m6A Regulators in Esophageal Cancer.

N6-methyladenosine (m6A) modification, the most prevalent RNA modification, is involved in all aspects of RNA metabolism, including RNA processing, nuclear export, stability, translation and degradation. Therefore, m6A modification can participate in various physiological functions, such as tissue development, heat shock response, DNA damage response, circadian clock control and even in carcinogenesis through regulating the expression or structure of the gene. The deposition, removal and recognition of m6A are carried out by methyltransferases, demethylases and m6A RNA binding proteins, respectively. Aberrant m6A modification and the dysregulation of m6A regulators play critical roles in the occurrence and development of various cancers. The pathogenesis of esophageal cancer (ESCA) remains unclear and the five-year survival rate of advanced ESCA patients is still dismal. Here, we systematically reviewed the recent studies of m6A modification and m6A regulators in ESCA and comprehensively analyzed the role and possible mechanism of m6A modification and m6A regulators in the occurrence, progression, remedy and prognosis of ESCA. Defining the effect of m6A modification and m6A regulators in ESCA might be helpful for determining the pathogenesis of ESCA and providing some ideas for an early diagnosis, individualized treatment and improved prognosis of ESCA patients.

MDM4 polymorphisms associated with the risk but not the prognosis of esophageal cancer in Cixian high-incidence region from northern China.

AIM: The mouse double minute 4 (MDM4) may contribute to tumorgenesis by inhibiting p53 tumor suppressor activity. This study was designed to investigate whether MDM4 polymorphisms could affect susceptibility to esophageal squamous cell carcinoma (ESCC) and the survival of ESCC patients in a population from Cixian high-incidence region of northern China, which has not been explored. METHODS: MDM4 rs1380576 and rs4245739 were genotyped by polymerase chain reaction-ligase detection reaction (PCR-LDR) in 568 ESCC patients and 578 controls. RESULTS: Compared to rs1380576 C/C genotype, C/G genotype was associated with decreased risk of ESCC (odds ratio [OR] = 0.761, 95% confidence interval [CI] = 0.595-0.973). Compared to rs4245739 A/A genotype, A/C or C/C genotype was related to increased susceptibility to ESCC (OR = 1.551, 95% CI = 1.001-2.402). Individuals with GC haplotype had significantly higher risk of ESCC than those with CA or GA haplotype (OR = 1.598, 95% CI = 1.048-2.438). Neither rs1380576 nor rs4245739 influenced the survival of ESCC patients. CONCLUSION: rs1380576 and rs4245739 may be used to predict susceptibility to ESCC for population in Cixian high-incidence region.

CDH1 Gene rs1801552 C/T Polymorphism Increases Susceptibility to Esophageal Squamous Cell Carcinoma but Not to Gastric Cardiac Adenocarcinoma.

PURPOSE: The present study aimed to investigate whether the single nucleotide polymorphism (SNP) rs1801552 C/T in CDH1 gene is correlated with the risk of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA), as a preliminary study. METHODS: The rs1801552 C/T polymorphism was genotyped by the method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 1316 cancer patients (810 ESCC and 506 GCA) and 1966 controls in north China. We performed two case-control studies, each of which included a population-based set and a hospital-based set. RESULTS: The data showed that the rs1801552 C/T polymorphism was associated with the risk of ESCC. Allelotype and genotype distributions of the rs1801552 C/T polymorphism in ESCC patients of high-incidence region and hospital were significantly different from that in their respective controls (p < 0.05). Compared with C/C genotype, T/T genotype increased the risk of ESCC in high-incidence region and hospital (age, sex, smoking status and family history of UGIC adjusted odds ratio (OR) = 1.79 and 2.10, 95% confidence interval (CI) = 1.23-2.60 and 1.10-4.04, respectively). Allelotype and genotype distributions of the rs1801552 C/T polymorphism in GCA patients were not significantly different from that in their controls, respectively (p > 0.05). CONCLUSIONS: The findings in the present pilot study suggest that the rs1801552 C/T polymorphism was associated with the risk of ESCC, but was not associated with the risk of GCA in high-incidence region and hospital.

TIM-3 polymorphism is involved in the progression of esophageal squamous cell carcinoma by regulating gene expression.

The T-cell immunoglobulin and mucin domain containing molecule 3 (TIM-3), a crucial immune regulatory molecule, is an emerging immune checkpoint target for cancer therapy. Our study aimed to investigate the association between TIM-3 polymorphisms (rs10053538 C > A, rs10515746 C > A, and rs1036199 A > C) and the susceptibility and prognosis of esophageal squamous cell carcinoma (ESCC). We further detect the effects of polymorphisms on TIM-3 expression. Two independent case-control sets (population-based and hospital-based sets) were performed in total 994 ESCC patients and 998 controls. TIM-3 polymorphisms were genotyped by polymerase chain reaction-ligase detection reaction (PCR). Survival data were available for 198 patients who received platinum-based chemotherapy after surgery. The regulation on TIM-3 expression by the polymorphisms was investigated in 35 patients using real-time quantitative PCR. The association between mRNA level of TIM-3 and survival was detected by using Kaplan-Meier plotter database. We found that for rs10053538 C > A polymorphisms, A allele was associated with significant increased risk of ESCC (odds ratios [OR] = 1.34, 95%CI = 1.05-1.72), and CA/AA genotypes enhanced susceptibility to ESCC for smokers (adjusted OR = 1.61, 95%CI = 1.00-2.59). The patients with AA genotypes had significantly poor prognosis (adjusted HR = 4.98, 95%CI = 1.14-21.71). The patients carrying CA/AA genotypes had significantly higher mRNA levels of TIM-3 than those carrying the CC genotype. Furthermore, high mRNA level of TIM-3 had a shorter overall survival in patients (HR = 2.56, 95%CI = 1.04-6.28). For rs10515746 C > A and rs1036199 A > C polymorphisms, there were no statistical correlation with the progression of ESCC. These data demonstrate that rs10053538 C > A polymorphisms may be associated with the susceptibility and prognosis of ESCC patients through regulating expression of TIM-3.

PARP1 rs1136410 C/C genotype associated with an increased risk of esophageal cancer in smokers.

DNA repair system plays a crucial role in maintaining genomic integrity and stability and in protecting against cancer. Poly(ADP-ribose) polymerase 1 (PARP1) functions as a key enzyme in the base excision repair (BER) pathway. Single nucleotide polymorphism (SNP) that could affect the function or expression of PARP1 gene might be associated with the risk of cancer. This study was designed to evaluate the association between PARP1 SNPs and the susceptibility to esophageal squamous cell carcinoma (ESCC) in a population from Cixian, a high incidence region from northern China. In 574 ESCC patients and 577 controls, PARP1 rs1136410 and rs8679 SNPs were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method. Upper gastrointestinal cancer (UGIC) family history enhanced the risk of ESCC (the sex-, age- and smoking status-adjusted OR 1.355, 95% CI 1.071-1.715). Overall, rs1136410 and rs8679 SNPs did not modify the risk of ESCC. When stratified by sex, age, smoking status and UGIC family history, the rs1136410 C/C genotype was associated with an increased risk of ESCC in smokers compared to T/T or T/C genotype (the sex-, age- and UGIC family history-adjusted OR 1.696, 95% CI 1.032-2.787). In Cixian high incidence region from northern China, smokers with rs1136410 C/C genotype might have higher susceptibility to ESCC than those with T/T or T/C genotype. These high-risk individuals receiving periodic upper gastrointestinal fiber tests might facilitate early detection and early treatment of ESCC.

The efficacy and safety of Osimertinib in advanced non-small cell lung cancer patients with Thr790Met resistance mutations: a systematic review and meta-analysis.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved by the U.S. Food and Drug Administration in treating T790M mutationpositive advanced non-small cell lung cancer (NSCLC). A systematic review and meta-analysis was conducted to assess the efficacy and safety of osimertinib in treating advanced NSCLC patients with acquired T790M mutation. METHODS: PubMed, EMBASE, Cochrane Library and Web of Science were searched to obtain the eligible studies following the "population, interventions, comparisons, outcomes, study design" (PICOS) criteria. The pooled analysis of objective response rate (ORR), disease controlled rate (DCR), progressionfree survival (PFS), overall survival (OS) and adverse events (AEs) were performed using STATA12.0 and RevMan5.0. RESULTS: A total of 1,050 patients were included in the meta-analysis. The combined osimertinib ORR was 0.64 (95% CI, 0.60-0.69), the ORR of central nervous system (CNS) was 0.54 (95% CI, 0.37-0.71), DCR was 0.89 (95% CI, 0.86-0.92), PFS at six months (PFS-6m) rate was 0.69 (95% CI, 0.58-0.79), PFS at one year (PFS-1y) rate was 0.33 (95% CI, 0.20-0.46), OS at one year (OS-1y) rate was 0.69 (95% CI, 0.55-0.84). The pooled incidence rate of the AEs of grade ≥ III was 0.25 (95% CI, 0.09-0.40). The results from Begg's and Egger's tests presented no publication bias in the included studies. CONCLUSIONS: Osimertinib demonstrated a superior therapeutic benefit with high efficacy and low toxicity for T790M-positive advanced NSCLC patients who were treated with early-generation EGFR-TKIs. Meanwhile, osimertinib showed promising for the treatment of advanced patients with CNS metastases.

PARP1 Gene Polymorphisms and the Prognosis of Esophageal Cancer Patients from Cixian High-Incidence Region in Northern China.

OBJECTIVE: Poly (ADP-ribose) polymerase 1 (PARP1), as a key enzyme in the base excision repair pathway, plays a crucial role in tumorigenesis and progression. This study aimed to assess whether polymorphisms of PARP1 gene could be used as predictive biomarkers for the survival of esophageal squamous cell carcinoma (ESCC) patients from Cixian high-incidence region in northern China. METHODS: In 203 ESCC patients with survival information, PARP1 rs1136410 T/C and rs8679 T/C single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method. All statistical analyses were performed using the SPSS ver. 22.0 software package (SPSS, Chicago, IL, USA). RESULTS: The mean age ± standard deviation of the ESCC patients was 60.4 ± 7.9 years. There was no significant relation of sex, age, smoking status and upper gastrointestinal cancer family history with the survival time of the ESCC patients. The mean survival time of rs1136410 T/T, T/C and C/C genotype carriers were 43.3, 42.3 and 46.6 months, respectively. The rs1136410 was not associated with the survival time of the ESCC patients. For rs8679, the mean survival time of T/T genotype carriers was 43.7 months, which was not significantly different from that of the patients with T/C genotype (42.1 months). CONCLUSION: In Cixian high-incidence region from northern China, rs1136410 and rs8679 SNPs might not be used to predict survival of ESCC patients. There is a need to explore whether other SNPs of PARP1 gene have an effect on prognosis of ESCC patients.

Association of cytotoxic T-lymphocyte associated protein 4 gene polymorphisms with the risk and prognosis of oesophageal cancer in a high-incidence region from northern China.

The most important anti-tumour immune response is mediated by T lymphocytes. Cytotoxic T lymphocyte-associated protein 4 (CTLA4) plays a critical role in the immune surveillance against tumours as an inhibitory immune checkpoint molecule of T-cell activation. This study was designed to explore the association of CTLA4 polymorphisms with the susceptibility to oesophageal squamous cell carcinoma (ESCC) and prognosis of patients with ESCC in a high-incidence population from northern China. CTLA4 rs5742909 C/T and rs231775 G/A single nucleotide polymorphisms (SNPs) were genotyped using polymerase chain reaction-ligase detection reaction (PCR-LDR) method in 577 ESCC patients and 580 controls. Upper gastrointestinal cancer family history increased the risk of ESCC (the sex-, age- and smoking status-adjusted OR = 1.383, 95%CI = 1.094-1.749). The genotype frequencies of these two SNPs in the patients with ESCC were similar to that in the controls. Survival analyses were conducted in 204 patients with ESCC with five-year survival information. The mean survival time of ESCC patients with rs231775 SNP A/A genotype in age over 60 years group was 23.2 months, significantly shorter than that of those with G/G genotype (47.3 months). The A/A genotype was associated with increased death risk of patients with ESCC older than 60 years (adjusted HR = 4.544, 95%CI = 1.913-10.790). CTLA4 rs231775 SNP might be used as genetic marker of worse prognosis for patients with ESCC over 60 years in a high-incidence population from northern China.

Genetic polymorphisms in hMSH2 and hMLH1 genes are associated with prognosis in epithelial ovarian cancer patients.

OBJECTIVE: DNA mismatch repair deficiency is not only thought to promote tumorigenesis but is also suggested to be associated with platinum-based chemotherapy treatment. In this study, we investigated the effects of two genetic polymorphisms in the hMSH2 and hMLH1 genes on the risk of epithelial ovarian cancer and the clinical outcome of patients treated with platinum-based chemotherapy. METHODS: A case-control study was performed in 536 epithelial ovarian cancer patients and 532 control women. Genotypes of two polymorphisms were determined by the polymerase chain reaction/ligase detection reaction method. Pearson Chi-square test was used to evaluate genotype distributions and allele frequencies in the patients and controls. Kaplan-Meier survival curves, and univariate and multivariate Cox regression models were used to analyze the effect of polymorphisms on patients' prognoses. RESULTS: The genotype and allele frequencies of the rs2303428 and rs1800734 polymorphisms were not significantly different between the case and control groups. Compared with wild homozygous genotype, the presence of variant alleles (heterozygous and variant homozygous genotypes) did not affect the risk of developing epithelial ovarian cancer. However, survival analysis showed that the rs2303428 polymorphism was related to the prognosis of epithelial ovarian cancer patients. Compared with the TT genotype, patients carrying the C allele had a shorter progression-free survival during the 3- and 5-year follow-up (HR 1.41, 95% CI 1.07 to 1.87 and HR 1.56, 95% CI 1.12 to 2.16, respectively). For the rs1800734 polymorphism, the A allele may significantly increase patients' progression-free survival compared with the GG genotype in the 5-year follow-up (HR 0.66, 95% CI 0.44 to 0.98). CONCLUSION: Our research suggests that genetic polymorphisms in hMSH2 and hMLH1 may indicate the clinical progression of epithelial ovarian cancer patients treated with platinum-based chemotherapy.

The effect of polymorphisms in the promoter of the BIRC5 gene on the risk of oesophageal squamous cell carcinoma and patient's outcomes.

Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is an inhibitor of apoptosis proteins and plays a key role in apoptosis or programmed cell death. In the present study, we evaluated the effect of BIRC5 gene polymorphisms on the risk of developing oesophageal squamous cell carcinoma (ESCC) and patients' outcomes in a high-incidence population from northern China. A population-based case-control study was performed in 597 ESCC patients and 597 control subjects.Survival data were available for 211 patients who received platinum-based chemotherapy after surgery. Five polymorphisms (-31 C>G, -241 C>T, -625 G>C, -644 T>C and -1547 A>G) in the promoter of the BIRC5 gene were genotyped by the polymerase chain reaction-ligase detection reaction (PCR-LDR) method. Compared with the -31 CC genotype, the -31 CG/GG genotype of -31 C>G single nucleotide polymorphism (SNP) was associated with a significant elevated risk of ESCC [adjusted odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.07-1.84]. Interestingly, this association was stronger among females, younger patients and non-smokers in stratified analyses (adjusted OR = 1.72, 95% CI = 1.07-2.75; adjusted OR = 1.61, 95% CI = 1.10-2.36; adjusted OR = 1.80, 95% CI = 1.26-2.58, respectively]. Survival analyses showed that the T allele of -241 C>T SNP was associated with poor prognosis [hazard ratio (HR) = 2.99, 95% CI = 1.09-8.19) and that the C allele of -625 G>C SNP was associated with good prognosis (HR = 0.62, 95% CI = 0.38-0.99) in ESCC patients. The -31 C>G polymorphism may be involved in the development of ESCC, and the -241 C>T and -625 G>C polymorphisms may be useful prognostic markers for ESCC.

Association between the vascular endothelial growth factor gene polymorphisms and the risk of polycystic ovary syndrome in Northern Chinese women.

The present study aimed to investigate whether the single nucleotide polymorphisms (SNPs) rs2010963 and rs833061 in vascular endothelial growth factor (VEGF) gene is correlated with the risk of polycystic ovary syndrome (PCOS) in Northern Chinese women, as a preliminary study. This case-control study comprised 118 women with PCOS and 130 healthy women as controls. Genotyping of the two polymorphisms within the VEGF gene 5'-untranslated region and promoter region were performed using polymerase chain reaction ligase detection reaction method. The data showed that there was a significant difference in the genotype and allele distribution of the rs2010963 polymorphism between the PCOS group and the control group (p = .020 and .033, respectively). The women carrying the C allele (G/C + C/C genotype) had a lower risk of PCOS compared with the women with G/G genotype [odds ratio (OR = 0.55; 95% confidence interval (CI) = 0.33-0.91]. Our study shows for the first time that the rs2010963 polymorphism may be associated with a risk of PCOS in Northern Chinese women.

Aberrant methylation of the IL-12B promotor region contributes to the risk of developing ovarian endometriosis.

Studies have shown that aberrant expression of IL-12p40, which is encoded by the interleukin-12B (IL-12B) gene, may be involved in the development of endometriosis. In this study, we investigated the role of aberrant methylation of the IL-12B promoter region and its associated expression in the development of ovarian endometriosis. By using pyrosequencing, we analyzed the methylation level of the IL-12B promoter region in eutopic and ectopic endometrium of patients with ovarian endometriosis and normal endometrium of control women. The expression of IL-12B mRNA was detected by quantitative real-time PCR. The results showed that the methylation level of the IL-12B promoter region in ectopic and eutopic endometrium of patients with ovarian endometriosis was significantly lower than that in endometrium of women without endometriosis ( p < 0.001 and p = 0.041, respectively). In contrast, mRNA levels were significantly increased in ectopic and eutopic endometrium of patients with ovarian endometriosis compared to those in endometrium of women without endometriosis ( p < 0.001 and p = 0.042, respectively). Correlation analysis showed that the methylation level of the IL-12B promoter region was negatively correlated with mRNA levels of IL-12B ( p < 0.001). Our data suggested that aberrant methylation of the IL-12B promoter region may be responsible for aberrant IL-12B mRNA expression in endometrium tissue of women, which may be associated with the development of ovarian endometriosis in northern Chinese women.

Phospholipase C ε-1 gene polymorphisms and prognosis of esophageal cancer patients from a high-incidence region in northern China.

Recent genome-wide association studies identified susceptibility loci for esophageal squamous cell carcinoma (ESCC), the most common histological type of esophageal cancer, in the phospholipase C ε-1 gene (PLCE1). The aim of the present study was to investigate whether polymorphisms of PLCE1 were associated with the prognosis of ESCC patients in a high-incidence region of northern China. The PLCE1 rs2274223 A/G and rs11599672T/G single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-ligase detection reaction method in 207 ESCC patients with survival information. The mean age ± standard deviation of the 207 ESCC patients was 60.3±7.9 years. Sex, age, smoking status and family history of upper gastrointestinal cancer were not found to be associated with the survival time of ESCC patients. The mean survival time of rs2274223 SNP A/A, A/G and G/G genotype carriers were 42.9, 43.4 and 46.3 months, respectively; for rs11599672 SNP T/T, T/G and G/G genotype carriers the survival time were 42.8, 43.8 and 42.7 months, respectively. There was no significant difference in survival time among the ESCC patients with different genotypes of rs2274223 and rs11599672 SNPs. In conclusion, PLCE1 rs227423 and rs11599672 SNPs cannot be used as predictive markers for the survival of ESCC patients from a high-incidence region of northern China.

Programmed death-1 ligand-1 gene rs2890658 polymorphism associated with the risk of esophageal squamous cell carcinoma in smokers.

BACKGROUND: The most important anti-tumor immune response is mediated by T lymphocytes. The interaction of programmed death-1 ligand-1 (PD-L1) with its receptor provides an inhibitory signal in T lymphocytes activation and proliferation. OBJECTIVE: This study aimed to investigate whether polymorphisms of PD-L1 were associated with the risk and prognosis of esophageal squamous cell carcinoma (ESCC) in a high-incidence population from Northern China. METHODS: PD-L1 rs2890658 A/C and rs4143815 C/G single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method in 575 ESCC patients and 577 healthy controls. RESULTS: There was no significant difference in the genotype frequencies of these two SNPs between the ESCC patients and the healthy controls. However, for rs2890658 A/C SNP, compared with the C/C genotype, the A/C genotype increased the risk of ESCC for the smokers (OR = 1.513, 95% CI = 1.006-2.287). Among the 575 ESCC patients, the survival information of 202 ESCC patients was collected. Neither the rs2890658 A/C SNP nor the rs4143815 C/G SNP was associated with the survival of ESCC patients. CONCLUSIONS: PD-L1 rs2890658 A/C SNP might be used as risk marker of the susceptibility to ESCC for the Han nationality in a high-incidence population from Northern China.

Association of programmed death-1 polymorphisms with the risk and prognosis of esophageal squamous cell carcinoma.

Programmed death-1 (PD-1) is an immunoinhibitory receptor belonging to the CD28 family. This study was designed to investigate the association of PD-1 rs36084323:A>G, rs2227981:C>T, rs2227982:C>T and rs10204525:A>G single nucleotide polymorphisms (SNPs) with the risk and prognosis of esophageal squamous cell carcinoma (ESCC) in a high-incidence population from Northern China. These four SNPs were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method in 584 ESCC patients and 585 healthy controls. The rs2227981:C>T SNP C/T genotype increased the risk of ESCC for the smokers (OR = 1.483, 95% CI = 1.018-2.160) and rs2227982:C>T SNP C/T genotype enhanced susceptibility to ESCC for the females (OR = 1.708, 95% CI = 1.056-2.762). For rs10204525:A>G SNP, A/A genotype was related to increased risk of ESCC (OR = 1.735, 95% CI = 1.086-2.771) overall. Among the 584 ESCC patients, the survival information of 204 ESCC patients was collected. The rs36084323:A>G SNP A/G genotype was associated with lower risk of death in ESCC patients with upper gastrointestinal cancer (UGIC) family history (HR = 0.339, 95%CI = 0.115-0.996). The rs2227982:C>T SNP C/T genotype was associated with lower risk of death in smoker ESCC patients and ESCC patients with UGIC family history (HR = 0.409 and 0.292, 95%CI = 0.194-0.863 and 0.101-0.847). PD-1 rs2227981:C>T, rs2227982:C>T and rs10204525:A>G SNPs might be used as predictive markers of the susceptibility to ESCC for the Han nationality in a high-incidence population from Northern China. PD-1 rs36084323:A>G and rs2227982:C>T SNPs were associated with the prognosis of the Han ESCC patients in this high-incidence region.

Role of the exogenous HCV core protein in the interaction of human hepatocyte proliferation and macrophage sub-populations.

BACKGROUND: The core protein of hepatitis C virus (HCV) is found in the cytoplasm and nuclei of infected cells, including hepatocytes and other cells in the liver. The core protein could be secreted as well. Resident liver macrophages are dependent on the tissue micro-environment and external stimuli to differentiate M1 and M2 hypotypes with distinct functions, and increased expression of the nuclear transcription factor STAT3 was seen in M2-polarized macrophages. In contrast to proinflammatory M1 macrophages, M2 macrophages serve beneficial roles in chronic inflammation, immunosuppression, and tumorigenesis. METHODS: Monocyte-derived human macrophage line (mTHP-1) was treated with the exogenous HCV core protein. Next, the mTHP-1 culture supernatant or cell pellets were added to culture media of normal human liver cell line (L02). RESULTS: Only the culture supernatant stimulated L02 cells proliferation, which was associated with phosphorylated ERK expression. Core protein activated mTHP-1 cells showed enhanced pro- and anti-inflammatory cytokines secretion, which was accompanied by high expression of phosphorylated NF-κB105 and NF-κB65. However, phosphorylated STAT1, and STAT3, which are normally associated with M1 and M2 macrophage polarization, and cell surface expression of CD206, CD14, CD16, and CD86, were unaltered. A transwell co-culture system showed that only in mTHP-1 co-cultured with L02 in the presence of exogenous core protein, were higher levels of phosphorylated STAT3 and CD206 seen. CONCLUSIONS: We showed L02 cells proliferation was accelerated by the culture supernatant of mTHP-1 cells treated with the exogenous HCV core protein. The exogenous core protein mediated the interaction between macrophages and hepatocytes in co-culture, which enhanced the expression of phosphorylated STAT3 and CD206 in macrophages.