Construction and Comprehensive Analysis of a Stratification System Based on AGTRAP in Patients with Hepatocellular Carcinoma.

BACKGROUND: With the development of sequencing technology, several signatures have been reported for the prediction of prognosis in patients with hepatocellular carcinoma (HCC). However, the above signatures are characterized by cumbersome application. Therefore, the study is aimed at screening out a robust stratification system based on only one gene to guide treatment. METHODS: Firstly, we used the limma package for performing differential expression analysis on 374 HCC samples, followed by Cox regression analysis on overall survival (OS) and disease-free interval (PFI). Subsequently, hub prognostic genes were found at the intersection of the above three groups. In addition, the topological degree inside the PPI network was used to screen for a unique hub gene. The rms package was used to construct two visual stratification systems for OS and PFI, and Kaplan-Meier analysis was utilized to investigate survival differences in clinical subgroups. The ssGSEA algorithm was then used to reveal the relationship between the hub gene and immune cells, immunological function, and checkpoints. In addition, we also used function annotation to explore into putative biological functions. Finally, for preliminary validation, the hub gene was knocked down in the HCC cell line. RESULTS: We discovered 6 prognostic genes (SKA1, CDC20, AGTRAP, BIRC5, NEIL3, and CDC25C) for constructing a PPI network after investigating survival and differential expression genes. According to the topological degree, AGTRAP was chosen as the basis for the stratification system, and it was revealed to be a risk factor with an independent prognostic value in Kaplan-Meier analysis and Cox regression analysis (P < 0.05). In addition, we constructed two visualized nomograms based on AGTRAP. The novel stratification system had a robust predictive value for PFI and OS in ROC analysis and calibration curve (P < 0.05). Meanwhile, AGTRAP upregulation was associated with T staging, N staging, M staging, pathological stage, grade, and vascular invasion (P < 0.05). Notably, AGTRAP was overexpressed in tumor tissues in all pancancers with paired samples (P < 0.05). Furthermore, AGTRAP was associated with immune response and may change immune microenvironment in HCC (P < 0.05). Next, gene enrichment analysis suggested that AGTRAP may be involved in the biological process, such as cotranslational protein targeting to the membrane. Finally, we identified the oncogenic effect of AGTRAP by qRT-PCR, colony formation, western blot, and CCK-8 assay (P < 0.05). CONCLUSION: We provided robust evidences that a stratification system based on AGTRAP can guide survival prediction for HCC patients.

Genetic polymorphisms in C-reactive protein increase cancer susceptibility.

Elevated levels of C-reactive protein (CRP) partially induced by polymorphisms in the CRP gene have been associated with human cancer. The purpose of this study was to test the hypothesis that CRP gene polymorphisms (+942G>C, 1846C>T) modify inherited susceptibility to cancer. We systematically identified the publications addressing the association of CRP gene polymorphisms with cancer susceptibility. Studies that fulfilled all inclusion criteria were considered eligible in this meta-analysis. We analyzed a total of 8 case-control studies. Individuals with the CC genotype were found to have an almost 4 fold higher risk of cancer than those with the GG or GC and GG genotypes. A significant association was also indicated in subgroup of colorectal cancer. Meta-analysis of 1846C>T polymorphism showed increased cancer risk in relation to the 1846 TT genotype (TT vs. CC: OR = 1.15, 95% CI = 1.01-1.31; TT vs. CT + CC; OR = 1.17, 95% CI = 1.03-1.32). Similar results were suggested in Caucasian populations and colorectal cancer. These data suggest that both +942G>C and 1846C>T polymorphisms in the CRP gene may influence cancer susceptibility.

A Comprehensive Analysis of Influence ERCC Polymorphisms Confer on the Development of Brain Tumors.

Within DNA repair genes, there lie a number of single nucleotide polymorphisms that may impair protein function and attenuate DNA repair capability, resulting in genomic instability and individual predisposition to malignancies. The purpose of this study was to assess the previously reported inconsistent association of polymorphisms in ERCC1 (rs11615, rs3212986), ERCC2 (rs13181, rs1799793, rs238406), and ERCC5 (rs17655) with the development of brain tumors. In the present work, we carried out a comprehensive meta-analysis of results from all published data (5 data sets for rs11615, 7 for rs3212986, 11 for rs13181, 5 for rs1799793, 3 for rs238406, and 4 for rs17655) to evaluate risk of brain tumors contributed by the polymorphisms being investigated. Either the analytic method described by Mantel and Haenszel or that proposed by DerSimonian and Laird was properly used to summarize the risk estimates (OR and 95% CI). Data analyses were done with Stata version 12.0. Meta-analyses were performed for all polymorphisms, and only rs3212986 in the ERCC1 gene showed a significant association with glioma incidence. In the homozygote comparison, we found 1.26-fold elevated risk of glioma in relation to presence of the AA genotype (OR = 1.26, 95% CI = 1.05-1.52, P OR = 0.013, P heterogeneity = 0.849, I(2) = 0.0%). We also noted that individuals with the rs3212986-AA as compared to those with rs3212986-CC/CA had a 28% higher risk to develop glioma (OR = 1.28, 95% CI = 1.06-1.53, P OR = 0.008, Pheterogeneity = 0.808, I(2) = 0.0%). No major effects were observed for Caucasians or Asians in subgroup analysis by ethnicity. ERCC1 rs3212986 is a common single nucleotide polymorphism and may contribute toward individual susceptibility for glioma. Further research in this filed is required to verify the association obtained based on a relatively small number.

Mitogen-Activated Protein Kinase Kinase 4 Gene Polymorphism and Cancer Risk.

A number of epidemiological studies have assessed the association of -1304T > G polymorphism in the MKK4 gene and risk of cancer, but the results lack of statistical power due to the limited subjects used in these studies. This study was devised to identify the genetic effects of the -1304T > G polymorphism on cancer risk in a large meta-analysis.Eligible studies were identified by searching both Chinese and English databases. General as well as subgroup analyses were performed for 8 independent case-control publications with a total of 4623 cases and 5256 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association.Overall, this meta-analysis showed that the association between the -1304T > G polymorphism and cancer risk was statistically significant (GG vs TT: OR = 0.63, 95% CI, 0.52-0.75; GG + TG vs TT: OR = 0.85, 95% CI, 0.79-0.91; GG vs TG + TT: OR = 0.67, 95% CI, 0.56-0.80; G vs T: OR = 0.82, 95% CI, 0.77-0.88; TG vs TT: OR = 0.86, 95% CI, 0.79-0.93).Our meta-analysis reveals that the presence of the -1304T > G polymorphism is likely to decrease risk of cancer. Future larger studies are necessary to validate the current finding.

Genetic association between TRAIL-R1 Thr209Arg and cancer susceptibility.

We aimed to determine the indecisive association between tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) Thr209Arg polymorphism and inherited susceptibility to cancer. A meta-analysis combining data on 9,517 individuals was performed to assess the association between TRAIL-R1 Thr209Arg and cancer incidence. The summary ORs with 95% CI calculated with the fixed effects model suggested that Thr209Arg was not significantly associated with cancer susceptibility (homozygous model: OR 0.98, 95% CI 0.88-1.09; heterozygous model: OR 0.95, 95% CI 0.87-1.04; allele frequency model: OR 0.99, 95% CI 0.94-1.05; dominant model: OR 0.98, 95% CI 0.91-1.05; recessive model: OR 1.01, 95% CI 0.92-1.10). Stratified analysis by ethnicity and cancer type yielded similar null associations. These statistical data suggest that Thr209Arg in exon 4 of the TRAIL-R1 gene may not represent a modifier of susceptibility to cancer.

Genetic Association Between NFKBIA -881A>G Polymorphism and Cancer Susceptibility.

Several epidemiological studies have focused on the role of nuclear factor-kappa-B inhibitor-alpha (NFKBIA) -881 A>G polymorphism in cancer susceptibility. However, the published data have led to contentious results. This study was designed to examine the association between -881 A>G polymorphism and cancer risk.Comprehensive search of PubMed, Web of science and Embase, identified a total of 5 case-control studies. To assess the association, comparison among all subjects plus subgroup analysis by ethnicity was performed and odds ratio (OR) along with 95% confidence interval (CI) was calculated with the fixed-effect model or the random-effects model dependent on the heterogeneity.The pooling data consisting of 1965 cancer cases and 2717 cancer-free controls demonstrated no significant association with overall cancer risk. However, the subgroup of Asian populations showed statistical evidence for an increase in risk of cancer (GG vs. AA, OR, 2.14; 95% CI, 1.03-4.46; GG + GA vs. AA, OR, 1.22; 95% CI, 1.01-1.47; GG vs. GA + AA, OR, 2.09; 95% CI, 1.01-4.34).This investigation on the association of -881 A>G polymorphism and cancer susceptibility reveals that -881 A>G polymorphism may act as a candidate for cancer development in Asian populations.

PSCA rs2294008 Polymorphism with Increased Risk of Cancer.

BACKGROUND: Published data on the association between PSCA rs2294008 polymorphism and cancer risk have implicated inconclusive results. To determine the relationship and to precisely assess the effect size estimate of the association, we performed a meta-analysis. METHODS: We searched published literature in Embase and PubMed databases using the search terms "PSCA", "prostate stem cell antigen", "variants", "polymorphism", "polymorphisms", and "cancer". A total of 21 eligible articles were retrieved, with 27, 197 cancer cases and 48, 237 controls. RESULTS: On the whole, we found the association between PSCA rs2294008 polymorphism and cancer risk was statistically significant: TT vs CC: OR = 1.18, 95% CI, 1.10 to 1.27; TT + CT vs CC: OR = 1.08, 95% CI, 1.05 to 1.10; TT vs CT + CC: OR = 1.14, 95% CI, 1.07 to 1.21; T vs C: OR = 1.10, 95% CI, 1.06 to 1.14; CT vs CC: OR = 1.10, 95% CI, 1.06 to 1.13. Stratified analyses in cancer type and ethnicity showed similar results. CONCLUSIONS: Based on the statistical evidence, we can draw a conclusion that the rs2294008 polymorphism of PSCA gene is likely to play a role in cancer carcinogenesis, especially in gastric cancer and bladder cancer.

TITF1 and TITF2 loci variants indicate significant associations with thyroid cancer.

A number of studies have investigated the influence of TITF1 and TITF2 genetic variants on thyroid carcinogenesis, but their associations remain unclear due to the controversial results. The objective of this study was to test the hypothesis that TITF1 and TITF2 variants modulate thyroid cancer susceptibility. Eligible studies were identified through online searches supplemented by manual search. Either the DerSimonian and Laird method or the Mantel-Haenszel method was used to estimate the risk of thyroid cancer (ORs and 95 % CIs). The pooled ORs were calculated assuming the allele model. We identified a total of 10 publications concerning the topic of interest. Overall, meta-analysis of rs944289 showed 1.11-fold increased risk of thyroid cancer related to the risk T allele (T vs. C: OR 1.11, 95 % CI 1.05-1.17). For rs965513, individuals carrying the risk A allele, compared to individuals with the G allele, had 31 % higher risk of thyroid cancer (A vs. G: OR 1.31, 95 % CI 1.17-1.46). Analyses in total samples for rs1867277, rs1443434, and rs907580 yielded similar associations (A vs. G: OR 1.22, 95 % CI 1.06-1.39; G vs. T: OR 1.26, 95 % CI 1.09-1.45; T vs. C: OR 1.42, 95 % CI 1.21-1.66, respectively). The significant association persisted among Caucasians in subgroup analyses for rs944289 and rs965513. The genetic susceptibility of thyroid cancer seems likely to be associated with the risk allele at rs944289 in the TITF1 gene and at rs1867277, rs965513, rs1443434, and rs907580 in the TITF2 gene.

Increased risk of cutaneous melanoma associated with p53 Arg72Pro polymorphism.

OBJECTIVE: The objective of this study was to test the hypothesis that p53 Arg72Pro polymorphism may contribute to an increased risk of cutaneous melanoma (CM). METHODS: By searching the databases of PubMed, EMBASE, and Web of Science, a total of 8 eligible case-control studies with 1,957 CM cases and 2,887 controls were included in this meta-analysis. Stata software was used to analyze all the statistical data. RESULTS: The pooled data by a fixed-effects model suggested an increased risk of CM associated with p53 Arg72Pro polymorphism under the genetic model of Arg/Pro vs. Pro/Pro without heterogeneity (ORArg/Pro vs. Pro/Pro = 1.76, 95% CI = 1.55-1.99, Pheterogeneity = 0.075). A similar trend was seen in subgroups of hospital-based studies and population-based studies. CONCLUSION: Our meta-analysis based on all studies shows that the p53 Arg72Pro polymorphism may increase individual susceptibility to CM, particularly in Caucasians and could serve as a biomarker to predict the population at high risk of CM.

Marked anti-tumor effects of CD8(+)CD62L(+) T cells from melanoma-bearing mice.

CD8(+)CD62L(+) T cells have been shown to play pivotal roles in anti-viral immunity, chronic myeloid leukemia and renal cell carcinoma. Recently, CD8(+)CD62L(+) T cells from naïve mice (nCD8(+)CD62L(+) T cells) have shown superior anti-tumor properties in melanoma-bearing mice. Considering that antigen-specific memory T cells have shown to possess more potent immunity than non-specific memory T cells, we hypothesized that CD8(+)CD62L(+) T cells from tumor-bearing individuals (mCD8(+)CD62L(+) T cells) might have superior anti-tumor effect than nCD8(+)CD62L(+) T cells. Therefore, we investigated phenotypes, functions and the in vivo distribution of mCD8(+)CD62L(+) T cells in tumor-bearing mice. We found that, while keeping the features of central memory T cells, the frequency of mCD8(+)CD62L(+) T cell in the spleen of tumor-bearing mice was significantly higher than that the one of nCD8(+)CD62L(+) T cell in naive mice. Moreover, we demonstrated that mCD8(+)CD62L(+) T cells had higher proliferation rate and IFN-γ production than nCD8(+)CD62L(+) T cells, in vitro. We performed adoptive transfer of mCD8(+)CD62L(+) T cells into melanoma-bearing mice and tracked them in spleen, lymph nodes and in melanoma tissues. Our results show that mCD8(+)CD62L(+) T cells had stronger in vivo anti-tumoral activity than nCD8(+)CD62L(+) T cells. This study highlights the therapeutic potential of mCD8(+)CD62L(+) T cells in the immunotherapy of melanoma and possibly other tumors.

Distinct role of CD86 polymorphisms (rs1129055, rs17281995) in risk of cancer: evidence from a meta-analysis.

BACKGROUND AND PURPOSE: Previous studies concerning the role of CD86 polymorphisms (rs1129055 and rs17281995) in cancer fail to provide compelling evidence. The aim of this study was to investigate the role of common polymorphisms in the risk of cancer by meta-analysis. METHODS: By using the search terms Cluster of Differentiation 86/CD86/B7-2/polymorphism/polymorphisms/cancer, we searched PubMed, Embase, CNKI, and Wanfang and identified four studies for rs1129055 (2137 subjects) and rs17281995 (2856 subjects) respectively. Cancer risk was estimated by odds ratio (OR) and 95% confidence interval (95% CI). MAJOR FINDINGS: Overall, we observed significant reduced risk of cancer in relation to rs1129055. Compared with the individuals with AA genotype, the individuals with GG genotype appeared to have 62% decreased risk to develop cancer (GG versus AA: OR, 0.62; 95% CI, 0.49-0.79; P(het)., 0.996). Similar effects were indicated in the G versus A allele model and the GG versus GA+AA genetic model (OR, 0.83; 95% CI, 0.74-0.93; P(het)., 0.987; OR, 0.63; 95% CI, 0.50-0.79; P(het)., 0.973). In addition, we found genotypes of rs17281995 had a major effect on overall cancer risk (CC versus GG: OR, 2.38; 95% CI, 1.43-3.95; P(het)., 0.433; C versus G: OR, 1.23; 95% CI, 1.06-1.43; P(het)., 0.521; CC versus GC+GG: OR, 2.38; 95% CI, 1.45-3.93; P(het)., 0.443). The association was also observed in Caucasians and colorectal cancer. No obvious publication bias was detected in this meta-analysis. CONCLUSIONS: These data reveal that rs1129055 may have protective effects on cancer risk in Asians and that rs17281995 is likely to contribute to risk of cancer, particularly colorectal cancer in Caucasians.

VSIG4 expression on macrophages facilitates lung cancer development.

Tumor-associated macrophages are a prominent component of lung cancer stroma and contribute to tumor progression. The protein V-set and Ig domain-containing 4 (VSIG4), a novel B7 family-related macrophage protein that has the capacity to inhibit T-cell activation, has a potential role in the development of lung cancer. In this study, 10 human non-small-cell lung cancer specimens were collected and immunohistochemically analyzed for VSIG4 expression. Results showed massive VSIG4(+) cell infiltration throughout the samples. Immunofluorescent double staining showed that VSIG4 was present on CD68(+) macrophages, but absent from CD3(+) T cells, CD31(+) endothelial cells, and CK-18(+) epithelial cells. Moreover, VSIG4 was coexpressed on B7-H1(+) and B7-H3(+) cells in these tumor specimens. Transfection of the VSIG4 gene into 293FT cells demonstrated that the VSIG4 signal could inhibit cocultured CD4(+) and CD8(+) T-cell proliferation and cytokine (IL-2 and IFN-γ) production in vitro. Interestingly, in a murine tumor model induced by Lewis lung carcinoma cell line, we found that tumors grown in VSIG4-deficient (VSIG4(-/-)) mice were significantly smaller than those found in wild-type littermates. All of these results demonstrate that macrophage-associated VSIG4 is an activator that facilitates lung carcinoma development. Specific targeting of VSIG4 may prove to be a novel, efficacious strategy for the treatment of this carcinoma.

Clinical implications of the tumor-infiltrating lymphocyte subsets in colorectal cancer.

Though the total lymphocyte density has been implicated in the pathogenesis of colorectal cancer (CRC), the clinical implications of lymphocyte subsets in CRC patients remain unclear yet. In this study, we used tissue microarrays and immunohistochemistry to evaluate the density of tumor-infiltrating CD4(+) and CD8(+) T cells as well as CD20(+) B cells in the central region and the invasive margin (IM) of tumor tissue from 67 CRC patients and then analyzed the clinical implications. We found that the subsets of tumor-infiltrating lymphocyte had no relationship with patients' age, tumor size, N category, and tumor stage. However, the density of B cells in the tumor center (TC) of colorectal patients in T1/T2 category was much higher than that of patients in T3/T4 category (P = 0.008). In addition, patients in M0 category had a higher density of CD8(+) T cells in the IM but not in the TC compared to patients in M1 category (P = 0.03). Results in this study demonstrate that higher CD8(+) T cell density in the IM of tumor is associated with lower tumor metastasis and higher B cell density in TC is associated with lower tumor T category. The results also suggest that the analysis of infiltrating lymphocyte subsets is important for understanding the detailed mechanisms of tumor pathogenesis and exploring potential interventions for the tumor.