Genome-wide long non-coding RNAs identified a panel of novel plasma biomarkers for gastric cancer diagnosis.

BACKGROUND: Although long non-coding RNAs (lncRNAs) are regarded as useful plasma-based biomarkers for cancer detection, the potential diagnostic value of lncRNAs in gastric cancer (GC) remains unclear. METHODS: To screen promising lncRNAs biomarkers for GC, we performed genome-wide lncRNA microarray assay between five GC cases plasma and matched healthy controls plasma. The expression of candidate plasma-related lncRNAs were validated in two-phase validation of 446 subjects. The receiver operating characteristic curve was constructed for evaluating diagnostic accuracy. We also determined the origin and stability of plasma lncRNAs, and investigated biological effects of candidate lncRNAs on cellular phenotypes. RESULTS: A total of 3878 lncRNAs were expressed differentially in GC plasma, among which the top 10 up-regulated lncRNAs were selected for further validation. A two-stage validation revealed that plasma levels of three lncRNAs (FAM49B-AS, GUSBP11, and CTDHUT) were significantly higher in GC plasma as compared with healthy controls (P < 0.05), and the combined area under curve of these lncRNAs was 0.818 (95% CI 0.772-0.864). Moreover, these lncRNAs were stable and detectable in human plasma, and also enriched in extracellular fluid. The expression levels of all three lncRNAs dropped significantly on day 10 after radical surgery compared with preoperative levels (P < 0.05). Also, lncRNA FAM49B-AS significantly promoted GC cell viability and invasion. CONCLUSIONS: Plasma lncRNA FAM49B-AS, GUSBP11 and CTDHUT have a strong potential to serve as noninvasive biomarkers for GC diagnosis.

A functional polymorphism in TFF1 promoter is associated with the risk and prognosis of gastric cancer.

Trefoil Factor 1 (TFF1, also named pS2), which serves as the gastrointestinal mucosal protector, is known as gastric-specific tumor suppressor gene. However, the genetic variants of TFF1 are still not well studied. In our study, we aim to explore the effects of tagging single nucleotide polymorphisms (tagSNPs) of TFF1 on risk and prognosis of gastric cancer. Seven tagSNPs of TFF1 gene were first analyzed in the discovery set, which was consisted of 753 cases and 950 cancer-free controls. Then, the validation set (940 cases and 1,042 controls) was used for further evaluation. Moreover, we also tested the relation between these tagSNPs and prognosis of gastric cancer (GC). A series of experiments were performed to investigate the underlying mechanisms. We found that rs3761376 AA in the promoter region of TFF1, could reduce the expression of TFF1 by affecting the binding affinity of estrogen receptor 1 (ESR1, ERα), and thereby increased the risk of GC (1.29, 1.08-1.53). Moreover, the rs3761376 AA genotype was also found associated with worse prognosis among patients receiving 5-FU based chemotherapy after surgery (1.71, 1.18-2.48). Further functional assays demonstrated that TFF1 could increase the chemosensitivity of 5-FU by modulating NF-κB targeted genes. These results identified the effect of rs3761376 on TFF1 expression, which accounted for the correlation with susceptibility and prognosis of GC; and this genetic variant may be a potential biomarker to predict the risk and survival of GC.

Evaluation of genome-wide genotyping concordance between tumor tissues and peripheral blood.

Tumor tissues were potential resources in cancer susceptibility studies. To assess the genotyping concordance between tumor tissues and peripheral blood, we conducted this study in a large sample size and genome-wide scale. Genome-wide genotypes of human colon adenocarcinoma (COAD) retrieved from The Cancer Genome Atlas (TCGA) was analyzed. A total of 387 pairs of matched fresh frozen tumor tissues and peripheral blood samples passed the quality control processes. High concordant rate (94.85% with no-calls and 97.89% without no-calls) was found between tumor tissues and peripheral blood. The discordant rate raised with the increase of heterozygote rate, and the tendency was statistically significant. The total missing rate was 3.10%. We also verified 14 susceptibility SNPs and the average genotyping concordant rate was 97.42%. These findings suggest that majority of SNPs could be accurately genotyped using DNA isolated from tumor tissues.

Dynamic contrast-enhanced MRI versus 18F-FDG PET/CT: Which is better in differentiation between malignant and benign solitary pulmonary nodules?

OBJECTIVE: To prospectively compare the discriminative capacity of dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) with that of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in the differentiation of malignant and benign solitary pulmonary nodules (SPNs). METHODS: Forty-nine patients with SPNs were included in this prospective study. Thirty-two of the patients had malignant SPNs, while the other 17 had benign SPNs. All these patients underwent DCE-MRI and 18F-FDG PET/CT examinations. The quantitative MRI pharmacokinetic parameters, including the trans-endothelial transfer constant (Ktrans), redistribution rate constant (Kep), and fractional volume (Ve), were calculated using the Extended-Tofts Linear two-compartment model. The 18F-FDG PET/CT parameter, maximum standardized uptake value (SUVmax), was also measured. Spearman's correlations were calculated between the MRI pharmacokinetic parameters and the SUVmax of each SPN. These parameters were statistically compared between the malignant and benign nodules. Receiver operating characteristic (ROC) analyses were used to compare the diagnostic capability between the DCE-MRI and 18F-FDG PET/CT indexes. RESULTS: Positive correlations were found between Ktrans and SUVmax, and between Kep and SUVmax (P<0.05). There were significant differences between the malignant and benign nodules in terms of the Ktrans, Kep and SUVmax values (P<0.05). The areas under the ROC curve (AUC) of Ktrans, Kep and SUVmax between the malignant and benign nodules were 0.909, 0.838 and 0.759, respectively. The sensitivity and specificity in differentiating malignant from benign SPNs were 90.6% and 82.4% for Ktrans; 87.5% and 76.5% for Kep; and 75.0% and 70.6% for SUVmax, respectively. The sensitivity and specificity of Ktrans and Kep were higher than those of SUVmax, but there was no significant difference between them (P>0.05). CONCLUSIONS: DCE-MRI can be used to differentiate between benign and malignant SPNs and has the advantage of being radiation free.

KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome.

BACKGROUND: Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC). METHOD: We performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan-Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients. RESULTS: The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P < 0.001). The survival curve indicated that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2. CONCLUSION: KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.

Expression and prognostic value of microRNA-26a and microRNA-148a in gastric cancer.

BACKGROUND AND AIM: In our previous study, we demonstrated that four microRNAs (miRNAs) (miR-26a, miR-142-3p, miR-148a, and miR-195) that were downregulated in both plasma and tumor tissues were confirmed to be promising non-invasive diagnostic biomarkers for gastric cancer (GC). METHODS: We used the quantitative reverse transcription polymerase chain reaction to assess the expression levels of the four miRNAs from paraffin-embedded surgical specimens of GC patients. Kaplan-Meier curves and log-rank test were applied to predict the correlation between miRNAs and cumulative overall survival (OS) of patients with GC. Besides, we performed in vitro assays including cell proliferation, migration, invasion and colony formation, and apoptosis. RESULTS: The median of miRNA expression in paraffin-embedded tissues were used as the cutoff value to classify patients into high or low expression groups. Down-regulation of miR-26a and miR-148a was significantly associated with shorter OS of GC patients either in the test set (miR-26a: P = 0.009; miR-148a: P = 0.005) or the validation set (miR-26a: P = 0.011; miR-148a: P = 0.024). When two sets were combined, Cox regression analysis demonstrated that both of miR-26a and miR-148a were independent prognostic factors for predicting OS of patients with GC (miR-26a: HR = 0.76, 95% CI = 0.61-0.94; miR-148a: HR = 0.73, 95% CI = 0.58-0.91). Furthermore, elevated expression of miR-26 significantly suppressed cell proliferation, migration, invasion and colony formation, and induced apoptosis of MGC-803 cells compared with negative control groups (P < 0.05). CONCLUSION: These findings supported miR-26a and miR-148a could serve as potential prognostic biomarkers for GC.

PSMB4 expression associates with epithelial ovarian cancer growth and poor prognosis.

PURPOSE: In this study, we investigated the expression and role of PSMB4 in human epithelial ovarian cancer(EOC). METHODS: Western blot was used to evaluate the expression of PSMB4 in EOC tissues, and immunohistochemical analysis was performed on 115 cases of ovarian cancers. Then, we used Fisher exact test to analyze the correlation between PSMB4 and clinicopathological parameters. Starvation and re-feeding assay was used to assess cell cycle. CCK-8 assay and plate colony formation assay showed the influence of PSMB4 on proliferation of EOC cells. RESULTS: The expression of PSMB4 in EOC tissues was higher than normal ovary tissues and was significantly associated with clinical pathologic variables. Kaplan-Meier curve showed that high expression of PSMB4 was related to poor prognosis of EOC patients. Starvation and re-feeding assay suggested that PSMB4 played a critical role in EOC cell proliferation. CCK-8 assay and plate colony formation assay showed that EOC cells treated with PSMB4-siRNA reduced cell proliferation of EOC cells. Additionally, PSMB4 knockdown decreased NF-κB activity. PSMB4 also regulated the expression of NF-κB mediated proteins, including cyclin D1, and cyclin E which involved in cell proliferation. CONCLUSIONS: Our findings implied that PSMB4 is involved in the progression of EOC and could serve as potential therapeutical target of EOC. These data suggested that PSMB4 may promote cell proliferation via the NF-κB-target gene in EOC.

Association of variants on ADIPOQ and AdipoR1 and the prognosis of gastric cancer patients after gastrectomy treatment.

Adiponectin is a protein hormone secreted exclusively by adipocytes and it is responsible for insulin sensitization in the human body. Deregulation of adiponectin and its downstream signaling pathway genes have been found to be involved in the gastric cancer carcinogenesis; however, whether the variants on adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) affect the prognosis of gastric cancer patients are still unknown. Here we have recruited 455 gastric cancer patients, who have received the gastrectomy treatment to evaluate the prognostic effects of variants on ADIPOQ (rs266729 and rs822395) and AdipoR1 (rs12733285 and rs1342387) for the gastric cancer patients. No significant association between the four variants and the overall survival of the gastric cancer patients was found. However, for those patients without a previous history of alcohol drinking, the rs266729 GG/CG genotype carriers showed a significantly decreased gastric cancer mortality compared to homogeneity CC patients (HR 0.74, 95 % CI 0.56-0.97; p = 0.032) after adjustment for variants age, sex, smoking status, tumor stage, tumor location and post-surgery chemotherapy. No significant association between the variant rs266729 genotypes and overall survival for the gastric cancer patients with an alcohol drinking habit. These data suggested that the variant rs266729 was an independent prognostic factor for the never drinking gastric cancer patients who received surgical treatment.

JWA suppresses tumor angiogenesis via Sp1-activated matrix metalloproteinase-2 and its prognostic significance in human gastric cancer.

JWA, a multifunctional microtubule-binding protein, plays an important role in regulating tumor metastasis via inhibition of matrix metalloproteinase-2 (MMP-2). Recent investigations suggest that MMP-2 is an angiogenesis-associated molecule. In this study, we provide novel evidence that JWA inhibits tumor angiogenesis in gastric cancer (GC). In two independent retrospective GC cohorts, we found that the expression of JWA was downregulated and that of MMP-2 was upregulated in GC tissues compared with the same in normal gastric mucosa. For patients treated with surgery alone, a strong and independent negative prognostic value was shown for low JWA and high MMP-2 expressions separately, which was even stronger when combined (hazard ratio = 7.75, P < 0.001, in the training cohort; hazard ratio = 2.31, P < 0.001, in the validation cohort). Moreover, we found that loss of JWA expression was strongly correlated with increased GC angiogenesis. In vitro, JWA inhibited MMP-2 at both messenger RNA and protein levels by modulating Sp1 activity. Knockdown of endogenous JWA resulted in enhanced human umbilical vein endothelial cell tube formation and MMP-2 expression. Furthermore, JWA was found to inhibit Sp1 activity via an ubiquitin-proteasome-dependent mechanism and to downregulate the expression of the proangiogenic MMP-2. Our findings imply that JWA and MMP-2 may serve as promising prognostic markers in resectable GC, with JWA as a useful biomarker of angiogenesis in GC and a potential therapeutic target by MMP-2 modulation.

CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer.

OBJECTIVE: CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). METHODS: The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. RESULTS: CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. CONCLUSIONS: Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.

MDM2 is a useful prognostic biomarker for resectable gastric cancer.

Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.

Genetic variants in HLA-DP/DQ contribute to risk of cervical cancer: a two-stage study in Chinese women.

OBJECTIVE: Human leukocyte antigens (HLA) play an important role in presenting virus antigens to immune cells that are responsible for the clearance of virus-infected cells and tumor cells. Herein, we evaluated whether genetic variants of HLA-DP and HLA-DQ are associated with cervical cancer risk. METHODS: We genotyped four single nucleotide polymorphisms (SNPs) in HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) in a two-stage case-control study with a total of 2317 cervical cancer cases and 2109 cancer-free controls using TaqMan allelic discrimination assay. RESULTS: We found consistently significant associations of HLA-DP rs3077 and rs9277535 with increased risks of cervical cancer (dominant genetic model: adjusted OR=1.51, 95% CI=1.32-1.71 for rs3077; adjusted OR=1.29, 95% CI=1.12-1.49 for rs9277535). When combining the effects of HLA-DP rs3077 and rs9277535, subjects carrying "≥1" variant alleles had a 1.55-fold increased risk of cervical cancer (95% CI=1.32-1.81), compared with those carrying "0" variant allele. And cervical cancer risk significantly increased with the increasing number of variant alleles of the two SNPs in a dose-dependent manner (P for trend=4.33×10(-10)). However, there were no significant associations for HLA-DQ rs2856718 and rs7453920 in our population. CONCLUSIONS: These findings indicate that HLA-DP rs3077 and rs9277535 were candidate susceptibility markers for cervical cancer in Chinese females. Further validation studies with different ethnic background, biological function analyses and especially HPV typing together were needed.

Association between XRCC1 and XRCC3 polymorphisms and colorectal cancer risk: a meta-analysis of 23 case-control studies.

Several potential functional polymorphisms in the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln (rs25487), Arg194Trp (rs1799782), Arg280His (rs25489) and X-ray repair cross-complementing group 3 (XRCC3) T241M (rs861539) have been implicated in colorectal cancer (CRC) risk, but the results are conflicting. Here, we performed a meta-analysis of 23 published case control datasets and assessed genetic heterogeneity between those datasets. All the case-control studies published from January 2000 to June 2012 on the association between those polymorphisms and CRC risk were identified by searching the electronic literature Medline. Statistical analysis was performed with the software programs Review Manager (version 4.2). For overall CRC, no significant association was observed, the pooled odds ratios for XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 T241M were 1.02 (95 % CI: 0.93, 1.12), 1.03 (95 % CI: 0.94, 1.14), 0.98 (95 % CI: 0.85, 1.13) and 1.03 (95 % CI: 0.85, 1.26), respectively. Furthermore, no significant association was observed in subgroup analyses based on ethnicity. The results suggested that these four SNPs evaluated are not associated with risk of CRC.

Polymorphisms involved in the miR-218-LAMB3 pathway and susceptibility of cervical cancer, a case-control study in Chinese women.

OBJECTIVE: Laminin-5 is required in RAS and NF-kappaB blockade induced tumorigenesis of human squamous cell carcinoma and a marker of invasiveness in cervical lesions. MicroRNA-218 (miR-218) can target laminin-5 beta3 (LAMB3), but suppressed by HPV-16 E6 protein. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in pri-miR-218 and LAMB3 may individually and/or jointly contribute to cervical cancer carcinogenesis. METHODS: We identified one SNP rs11134527 located in pri-miR-218 sequence and one SNP rs2566 in 3'UTR of LAMB3 and genotyped these two SNPs in a case-control study of 703 cervical cancer cases and 713 cancer-free controls in Chinese women. RESULTS: Logistic regression analyses showed that the pri-miR-218 rs11134527 variant homozygote GG was associated with a decreased risk of cervical cancer compared with the AA genotype (adjusted OR=0.72, 95% CI=0.52-0.99), while the LAMB3 rs2566 variant CT/TT genotypes were associated with a significantly increased risk of cervical cancer (adjusted OR=1.57, 95% CI=1.25-1.96), compared with the wild type CC genotype. A significant dose-response effect was observed between the number of risk alleles, rs11134527A and rs2566 T, and the risk of cervical cancer (P for trend=0.0006). CONCLUSION: These findings indicate that pri-miR-218 rs11134527 and LAMB3 rs2566 may contribute to cervical cancer carcinogenesis, and further validations in diverse populations and functional characterizations are warranted.

SMADs binding site polymorphisms rs9911630 is associated with susceptibility but not prognosis of gastric cancer: a case control study.

Background: Single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBS) can change their binding strength, affecting the function of transcription factors (TFs). Small mother against decapentaplegic (SMAD) proteins are known as a family of TFs involved in tumorigenesis. We performed this study to investigate whether SNPs in SMADs binding sites affect the susceptibility or prognosis of gastric cancer (GC). Methods: Using bioinformatics tools, we focused on the association between rs9911630 polymorphism and GC. We performed this case-control study in 1275 GC patients and 1426 cancer-free subjects using TaqMan allelic discrimination method. Results: We found that rs9911630 A>G polymorphism was associate to an increased risk of gastric cancer (adjusted OR for additive model = 1.16; 95% CI = 1.03-1.30). Furthermore, we assess whether rs9911630 polymorphism affected the prognosis of GC. However, no significant association was discovered between rs9911630 A>G polymorphism and overall survival time of GC patients (HR for addictive model = 1.01; 95%CI = 0.88-1.15). Conclusions: Our results suggested that rs9911630 polymorphism in SMADs target site might influence susceptibility but not prognosis of gastric cancer.

Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer.

The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, P = 2.13 × 10-9]. This risk effect was mediated through the mapped long noncoding RNA GCLET (Gastric Cancer Low-Expressed Transcript; ORindirect = 0.987, 95% CI = 0.975 to 0.999, P = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on GCLET by affecting the binding affinity of CTCF. Furthermore, GCLET increased FOXP2 expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.

Clinical significance and effect of Sam68 expression in gastric cancer.

Gastric cancer is one of the most common types of malignancy worldwide. However, the molecular mechanisms of cancer development remain unclear. Src-associated in mitosis of 68 kDa (Sam68) is involved in cell proliferation, transformation, tumorigenesis and metastasis in several types of cancer. The present study aimed to assess the expression and function of Sam68 in human gastric cancer. Western blot analysis and immunohistochemistry indicated that Sam68 expression was increased in tumor samples and the levels were associated with the grade of malignancy. High Sam68 expression was associated with the poor prognosis of patients with gastric cancer. In vitro, following knockdown of Sam68 by transfection of gastric cancer cells with small interfering RNA, the cell viability, cell cycle progress, migration and invasion were decreased. The results of the present study revealed that Sam68 may be a novel prognostic factor for, and is associated with cell growth, migration and invasion in, gastric cancer.

Evaluation of GWAS-Identified Genetic Variants for Gastric Cancer Survival.

BACKGROUNDS: Genome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS-identified genetic variants could serve as robust prognostic biomarkers for GC. METHODS: A multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS-identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log-rank P was calculated by the log-rank test with the Kaplan-Meier method. RESULTS: We found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223. INTERPRETATION: This preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation.

Cancer survival in patients from a hospital-based cancer registry, China.

Purpose: There are few reports on survival rate analysis from hospital-based cancer registries (HBCR) in China, although the National Center of Cancer Registry of China has launched such an effort with the mission to expand the scope of registration and follow-up. Our study aimed to evaluate survival and outcomes of cancer patients from a HBCR in eastern China. Methods: Active and passive follow-up methods were used to obtain information on survival status for all patients from Qidong City and Haimen City in the databases of our hospital-based registrations from 2002 to 2014. Censor time for survival was 31st March, 2016. Survival probability was estimated using the life-table method with SPSS Statistics software, and comparison of significant differences in survival rates was tested by Wilcoxon (Gehan) statistic. Results: The outcomes of 5010 patients were identified in the follow-up for 5244 cases from Qidong and Haimen, with a follow-up rate of 95.65%, and a rate of lost to follow-up of 4.35%. The 1-, 3-, 5-, and 10-year observed survival (OS) rate in all-combined cancer sites were 59.80%, 37.70%, 30.82%, and 22.60%, respectively. The top 10 cancer sites in rank were cancers of lung, esophagus, liver, cervix, stomach, breast, colon-rectum, non-Hodgkin's lymphoma, nasopharynx, and ovary, with 5-year OS rates of 12.63%, 19.62%, 11.69%, 66.61%, 21.35%, 59.43%, 36.36%, 37.03%, 48.95% and 36.17%, respectively. Females experienced better survival than males for lung, esophageal, liver, nasopharyngeal and pancreatic cancers (P<0.05), but not for other sites (P>0.05). A significant difference was also found between males and females when all-sites were combined (P<0.01). There are significant differences (P<0.05) between the 2015 patients (from Qidong) and the 3001 patients (from Haimen) with 5-year OS rates of 32.72% vs 29.57%; no significant differences were found for 5-year OS rates for individual cancer sites (P>0.05) except for liver (P=0.0005) and ovary (P=0.0460) between the two cities. Younger patients had better prognosis, but significance was only seen in cervical (P=0.0102) and nasopharyngeal (P=0.0305) cancers. Conclusion: The survival rates of each site or of all sites-combined in this setting are consistent with those elsewhere in China and abroad. Discrepancies in overall survival could be affected by the proportion of sites with or without better prognosis. Hospital-based cancer survival is a better index to evaluate outcomes that reflect the levels of comprehensive treatment and improvement of medical and health services.

A Genetic Variant Located in miR-146b Promoter Region Is Associated with Prognosis of Gastric Cancer.

Background: SNPs in the promoter region of miRNAs have been reported to be associated with cancer prognosis. Our previous study found that miR-146b had a strong correlation with the stage classification of gastric cancer and contributed to tumor progression. The current study was aimed at investigating whether an SNP located in the promoter region of miR-146b could affect the survival rate of gastric cancer.Methods: Using bioinformatics tools, we identified one SNP (rs1536309) that is located in the miR-146b promoter. We genotyped this SNP site to assess its association with gastric cancer prognosis in 940 cases.Results: We found that the dominant model of miR-146b rs1536309 was associated with a higher survival rate of gastric cancer. The association remained significant in the subgroup analysis by age (≤60), sex (male), tumor size (≤5 cm), histologic type (diffuse), lymph node metastasis (N0), distant metastasis (M0), and TNM stage (I/II).Conclusions: Our results suggested that the miR-146b rs1536309 polymorphism may be a potential biomarker for the prognosis of gastric cancer.Impact: This is the first evidence showing that patients carrying the miR-146b-5p rs1536309 CC/CT genotypes exhibited better survival than those carrying the TT genotype, suggesting the protective effect of the C allele in the prognosis of gastric cancer. Cancer Epidemiol Biomarkers Prev; 27(7); 822-8. ©2018 AACR.