HOXC10 indicates poor survival outcome in gastric cancer and promotes G1/S cell cycle transition through transcriptional repression of p21.

Homeobox (HOX) genes encode proteins that function as transcription factors during embryogenesis and tumorigenesis. We have previously reported upregulation of HOXC10 in gastric cancer (GC) tissues using cDNA microarray analysis. Though the functional role of HOXC10 in GC has been briefly reported, its specific mechanism is not fully understood. We analyzed the expression of HOXC10 in GC tissues, as well as its correlation with the survival outcome. By in vitro and in vivo assays, we further investigated the role of HOXC10 on cell cycle control and proliferation. Finally, we screened potential downstream targets of HOXC10 by cDNA microarray and explored the role of HOXC10 in p21 transcriptional repression through a dual luciferase reporter and chromatin immunoprecipitation. We illustrated the upregulation of HOXC10 in GC tissues and high HOXC10 expression related to poor survival outcome. Multivariable COX regression analysis showed that HOXC10 was an independent predictor of survival (HR=1.863; 95% CI: 1.076-3.225). Functionally, HOXC10 could promote GC cell proliferation and tumor growth in nude mice. Overexpression of HOXC10 accelerated G1/S cell cycle transition, whereas knocking down HOXC10 induced cell cycle arrest at the G1 phase. Critical factors of G1/S cell cycle transition including p21, CDK2, and c-Myc, were regulated by HOXC10. Importantly, an inverse correlation between p21 and HOXC10 expression in GC cell lines and tissues was observed. HOXC10 could directly bind to the promoter region of p21 and repress its transcriptional activity. Collectively, we identified HOXC10 as a predictor of poor prognosis in GC patients, and a novel transcriptional regulator of p21 in the G1/S cell cycle transition.

Prognostic and biological role of the N-Myc downstream-regulated gene family in hepatocellular carcinoma.

BACKGROUND: The N-Myc downstream-regulated gene (NDRG) family is comprised of four members (NDRG1-4) involved in various important biological processes. However, there is no systematic evaluation of the prognostic of the NDRG family in hepatocellular carcinoma (HCC). AIM: To analyze comprehensively the biological role of the NDRG family in HCC. METHODS: The NDRG family expression was explored using The Cancer Genome Atlas. DNA methylation interactive visualization database was used for methylation analysis of the NDRG family. The NDRG family genomic alteration was assessed using the cBioPortal. Single-sample Gene Set Enrichment Analysis was used to determine the degree of immune cell infiltration in tumors. RESULTS: NDRG1 and NDRG3 were up-regulated in HCC, while NDRG2 was down-regulated. Consistent with expression patterns, high expression of NDRG1 and NDRG3 was associated with poor survival outcomes (P < 0.05). High expression of NDRG2 was associated with favorable survival (P < 0.005). An NDRG-based signature that statistically stratified the prognosis of the patients was constructed. The percentage of genetic alterations in the NDRG family varied from 0.3% to 11.0%, and the NDRG1 mutation rate was the highest. NDRG 1-3 expression was associated with various types of infiltrated immune cells. Gene ontology analysis revealed that organic acid catabolism was the most important biological process related to the NDRG family. Gene Set Enrichment Analysis showed that metabolic, proliferation, and immune-related gene sets were enriched during NDRG1 and NDRG3 high expression and NDRG2 low expression. CONCLUSION: Overexpression of NDRG1 and NDRG3 and down-expression of NDRG2 are correlated with poor overall HCC prognosis. Our results may provide new insights into the indispensable role of NDRG1, 2, and 3 in the development of HCC and guide a promising new strategy for treating HCC.

Effect of prior malignancy on the prognosis of gastric cancer and somatic mutation.

BACKGROUND: Cancer survivors have a higher risk of developing secondary cancer, with previous studies showing heterogeneous effects of prior cancer on cancer survivors. AIM: To describe the features and clinical significance of a prior malignancy in patients with gastric cancer (GC). METHODS: We identified eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database, and compared the clinical features of GC patients with/without prior cancer. Kaplan-Meier curves and Cox analyses were used to assess the prognostic impact of prior cancer on overall survival (OS) and cancer-specific survival (CSS) outcomes. We also validated our results in The Cancer Genome Atlas (TCGA) cohort and compared mutation patterns. RESULTS: In the SEER dataset, of the 35492 patients newly diagnosed with GC between 2004 and 2011, 4,001 (11.3%) had at least one prior cancer, including 576 (1.62%) patients with multiple cancers. Patients with a prior cancer history tended to be elderly, with a more localized stage and less positive lymph nodes. The prostate (32%) was the most common initial cancer site. The median interval from initial cancer diagnosis to secondary GC was 68 mo. By using multivariable Cox analyses, we found that a prior cancer history was not significantly associated with OS (hazard ratio [HR]: 1.01, 95% confidence interval [CI]: 0.97-1.05). However, a prior cancer history was significantly associated with better GC-specific survival (HR: 0.82, 95% CI: 0.78-0.85). In TCGA cohort, no significant difference in OS was observed for GC patients with or without prior cancer. Also, no significant differences in somatic mutations were observed between groups. CONCLUSION: The prognosis of GC patients with previous diagnosis of cancer was not inferior to that of primary GC patients.

Impact of Barrett's esophagus surveillance on the prognosis of esophageal adenocarcinoma: A meta-analysis.

OBJECTIVE: Whether endoscopic surveillance would improve the outcomes of esophageal adenocarcinoma in patients previously diagnosed with Barrett's esophagus remains unclear. This meta-analysis aimed to assess the survival advantages of endoscopic surveillance for patients with Barrett's esophagus. METHODS: Databases including PubMed, the Web of Science, and the Cochrane Library were examined systematically from their inception to July 2017, for articles related to the survival outcomes of esophageal adenocarcinoma in patients with Barrett's esophagus under endoscopic surveillance. Adjusted hazard estimates were adopted to determine overall results with 95% confidence intervals (CIs), using the fixed-effect model. We conducted subgroup and sensitivity analyses using the "metan" command in Stata software to assess the stability of the overall results. Begg's test, Egger's test and the funnel plot were used to evaluate the presence of publication bias. RESULTS: A total of eight studies (two case-control and six cohort studies) were finally included in our current study. Compared with patients with esophageal adenocarcinoma that was not detected by surveillance, a significant 29% reduction in mortality from esophageal adenocarcinoma was observed among patients under endoscopic surveillance (adjusted hazard ratio [HR] 0.71, 95% CI 0.66-0.77). This effect was presented in both the USA (adjusted HR 0.71, 95% CI 0.65-0.78) and Europe (adjusted HR 0.71, 95% CI 0.60-0.83). We found no evidence of publication bias. CONCLUSIONS: Our meta-analysis supports the concept that endoscopic surveillance for patients with Barrett's esophagus could improve the prognosis of esophageal adenocarcinoma. More well-designed prospective studies are needed to confirm this association.

Different Anatomical Subsites of Colon Cancer and Mortality: A Population-Based Study.

BACKGROUND: In terms of incidence and pathogenesis, right-sided colon cancer (RCC) and left-sided colon cancer (LCC) exhibit several differences. However, whether existing differences could reflect the different survival outcomes remains unclear. Therefore, we aimed to ascertain the role of location in the prognosis. METHODS: We identified colon cancer cases from the Surveillance, Epidemiology, and End Results database between 1973 and 2012. Differences among subsites of colon cancer regarding clinical features and metastatic patterns were compared. The Kaplan-Meier curves were conducted to compare overall and disease-specific survival in relation to cancer location. The effect of tumour location on overall and cancer-specific survival was analysed by Cox proportional hazards model. RESULTS: A total of 377,849 patients from SEER database were included in the current study, with 180,889 (47.9%) RCC and 196,960 (52.1%) LCC. LCC was more likely to metastasize to the liver and lung. Kaplan-Meier curves demonstrated that LCC patients had better overall and cancer-specific survival outcomes. Among Cox multivariate analyses, LCC was associated with a slightly reduced risk of overall survival (HR, 0.92; 95% CI, 0.92-0.93) and cancer-specific survival (HR, 0.92; 95% CI, 0.91-0.93), even after adjusted for other variables. However, the relationship between location and prognosis was varied by subgroups defined by age, year at diagnosis, stage, and therapies. CONCLUSIONS: We demonstrated that LCC was associated with better prognosis, especially for patients with distant metastasis. Future trails should seek to identify the underlying mechanism.

Marital status and survival in patients with primary liver cancer.

BACKGROUND: Marital status is viewed as an independent prognostic factor for survival in various cancer types. However, its role in primary liver cancer has yet to be thoroughly explored. OBJECTIVE: To investigate the impact of marital status on survival outcomes among liver cancer patients. RESULTS: We finally identified 40,809 eligible liver cancer patients between 2004 and 2012, including 21,939 (53.8%) patients were married at diagnosis and 18,870 (46.2%) were unmarried (including 5,871 divorced/separated, 4,338 widowed and 8,660 single). Married patients enjoyed overall and cause-specific survival outcomes compared with patients who were divorced/separated, widowed, single, respectively. The survival benefit associated with marriage still persisted even after adjusted for known confounders. Widowed individuals were at greater risk of overall and cancer-specific mortality compared to other groups. Similar associations were observed in subgroup analyses according to SEER stage. MATERIALS AND METHODS: We used the Surveillance, Epidemiology and End Results (SEER) database to identify 40,809 patients diagnosed with primary liver cancer between 2004 and 2012. Kaplan-Meier analysis and Cox regression were performed to identify the influence of marital status on overall survival (OS) and liver cancer-specific survival (CSS). CONCLUSIONS: In primary liver cancer patients, married patients enjoyed survival benefits while widowed persons suffered survival disadvantages in both overall survival and cancer-specific survival.

Contrast-enhanced endoscopic ultrasound for differential diagnosis of pancreatic cancer: an updated meta-analysis.

AIM: We aim to assess the diagnostic value of contrast-enhanced endoscopic ultrasound (CE-EUS) for pancreatic cancer and inflammatory lesions by pooling current evidence. MATERIALS AND METHODS: A systematical search of PubMed, Web of Science and the Cochrane Library was performed from inception to January 2016. Two authors independently screened and extracted detailed data from included studies. A random effect model was adopted to estimate the pooled sensitivity, specificity in order to determine the diagnostic ablitity of CE-EUS. Furthermore, we conducted the meta-regression and subgroup analyses to explore possible heterogeneity. RESULTS: Eighteen eligible studies enrolling 1668 patients were finally included in the study. The pooled sensitivity of CE-EUS for distinguishing pancreatic cancers from solid inflammatory masses was 0.93 (95% CI, 0.91-0.94), and the specificity was 0.88 (95% CI, 0.84-0.90). The area under summary receiver operating characteristic curve yielded 0.97. No publication bias was observed by Deeks' funnel plot in current meta-analysis. CONCLUSIONS: We provided evidence that CE-EUS is a promising modality for differential diagnosis of pancreatic adenocarcinomas. Further multicenter prospective studies should be carried out to certify its utility.

Diagnostic performance of confocal laser endomicroscopy for optical diagnosis of gastric intestinal metaplasia: a meta-analysis.

BACKGROUND: Gastric intestinal metaplasia (IM) is generally considered as a precancerous condition, a related risk factor for intestinal-type gastric cancer. However, an accurate endoscopic diagnosis of IM is a clinical challenge. Confocal Laser Endomicroscopy (CLE) is a newly technique that can provide real-time magnified images and visualize tissues at cellular or subcellular levels. The aim of this study is to clarify the diagnostic value of CLE in detection of IM in patients at high risk of gastric cancer. METHODS: Systematic literature searches up to April 2015 in PubMed, Embase, Web of Science, Cochrane Library databases were conducted by two reviewers independently. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was applied to assess study quality and to reduce potential bias. A meta-analysis using Meta-Disc (version 1.4) and STATA software (version 13) was performed. RESULTS: A total of four studies enrolled 218 patients and 579 lesions were included in this meta-analysis. On per-lesion basis, the pooled sensitivity and specificity of CLE were 0.97(95 % confidence interval (CI) = 0.94-0.98) and 0.94 (95 % CI = 0.91-0.97) respectively. The pooled positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 15.20 (95 % CI = 9.46-24.41) and 0.04 (95 % CI = 0.02-0.07) respectively. The pooled diagnostic odds ratio (DOR) was 479.59 (95 % CI = 205.64-1118.51) and summary receiver operating curve (SROC) area under the curve was 0.9884. There was no statistical significance of publication bias. CONCLUSION: CLE is a promising endoscopic tool in the detection of IM with the relatively high diagnostic value in patients at high risk of gastric cancer.

Metformin Is Associated With Slightly Reduced Risk of Colorectal Cancer and Moderate Survival Benefits in Diabetes Mellitus: A Meta-Analysis.

To systematically assess the effect of metformin on colorectal cancer (CRC) risk and mortality in type 2 diabetes mellitus (T2DM) patients. We conducted a systematic search of PubMed, Web of Science, and the Cochrane Library databases for relevant articles before August 2015. Two investigators identified and extracted data independently. We adopted adjusted estimates to calculate summary estimates with 95% confidence interval (CI) using either a fixed-effects or a random-effects model. Subgroup and sensitivity analyses were conducted to evaluate the robustness of the pooled results. The risk of publication bias was assessed by examining funnel plot asymmetry as well as Begg test and Egger test. Fifteen studies on CRC incidence and 6 studies on CRC survival were finally included in our meta-analysis. The pooled odds ratio (OR) of observational studies illustrated that a slight 10% reduction of CRC incidence was associated with metformin use (OR = 0.90, 95% CI: 0.85-0.96). Furthermore, the pooled hazard ratio (HR) revealed an improved survival outcome for metformin users in CRC patients compared to nonusers (HR = 0.68, 95% CI: 0.58-081). There was no publication bias across studies. Our meta-analysis demonstrated that metformin therapy could slightly reduce CRC incidence and moderately improve the survival outcomes in patients with T2DM. More prospective studies are warranted to certify this protective association.