Methylation of the RAS association domain family protein 1A (RASSF1A) promoter has been observed in nasopharyngeal carcinoma (NPC). This study investigated the correlation of RASSF1A promoter methylation with clinicopathological features and its utility as a diagnostic biomarker in NPC. A total of 926 patients with NPC and 495 non-tumor controls were analyzed in this study. RASSF1A promoter methylation was notably higher in NPC compared with non-tumor tissue, brushing and blood samples. RASSF1A promoter methylation was associated with clinical stage, lymph node status, distant metastasis, and T classification of patients with NPC, although it was not linked to age and sex. The pooled sensitivity, specificity, and AUC (area under the curve) of RASSF1A promoter methylation were determined in NPC samples vs. non-tumor samples (tissue: sensitivity=0.72, specificity=0.99, AUC=0.98; brushing: sensitivity=0.56, specificity=1.00, AUC=0.94; blood: sensitivity=0.11, specificity=0.98, AUC=0.97). Our findings show that RASSF1A promoter methylation may be correlated with the development, progression and metastasis of NPC. RASSF1A promoter methylation is a promising noninvasive biomarker for the diagnosis of NPC from tissue and brushing samples.

Background: A number of studies have attempted to determine the prognostic significance of proliferating cell nuclear antigen (PCNA) in patients with colorectal cancer (CRC), but the reports are controversial and inconsistent. Thus, we conducted a meta-analysis to clarify the value of PCNA in CRC prognosis. Methods: A systematic search of relevant studies was performed in 4 electronic databases including PubMed, Cochrane Library, Embase, and Web of Science until February 2018. Hazard ratios (HRs) combined with 95% confidence intervals (95% CIs) were used to evaluate the relationship of PCNA expression with overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Results: A total of 1372 CRC patients in 14 studies were identified eventually in our meta-analysis. The pooled HRs demonstrated that CRC patients with high PCNA expression was significantly correlated with poor OS (HR = 1.81; 95% CI: 1.51–2.17; P = .000), CSS (HR = 1.99; 95% CI: 1.04–3.79; P = .037); but not significantly with DFS (HR = 2.48; 95% CI: 0.98–6.26; P = .055). Sensitivity analysis showed the pooled HRs for OS, CSS, and DFS were stable when the included studies were removed one by one. Conclusion: Our meta-analysis suggested that high PCNA expression was associated with poor prognosis, and it could serve as a reliable and prognostic biomarker in CRC patients. More large-scale studies are needed to further support the conclusion.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Meng Ye1, Tao Huang1, Ying Ying3, Jinyun Li1, Ping Yang1, 2, Chao Ni1, 2, Chongchang Zhou2, Si Chen1 1The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315020, People’s Republic of China 2Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, People’s Republic of China 3Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, People’s Republic of China Correspondence to: Meng Ye, email: yemeng@nbu.edu.cn Tao Huang, email: huangtao334@163.com Keywords: 14-3-3 σ, promoter methylation, breast cancer, blood, diagnosis, biomarker Received: September 27, 2016 Accepted: December 12, 2016 Published: December 16, 2016

Loss of tumor suppressor gene p16 expression via promoter methylation has been reported in hepatocellular carcinoma (HCC). This meta-analysis was conducted to evaluate the correlation between p16 methylation and HCC. Additionally, we also analyzed the potential prognostic role of p16 methylation, expression or alteration-associated HCC. Online databases based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline were performed to analyze the role of p16 gene in HCC. The combined odds ratios (ORs) or hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were summarized. Final 3105 HCCs and 808 non-tumor controls (chronic hepatitis and liver cirrhosis) were performed in this meta-analysis. p16 promoter methylation in HCC was significantly higher than in chronic hepatitis and chronic hepatitis in tissue and blood samples. In addition, p16 promoter methylation was notably higher in patients >50 years’ old than in patients aged <50 years, and it was higher in hepatitis B virus (HBV) or hepatitis C virus (HCV)-positive HCC than in hepatic viruses-negative HCC. However, p16 promoter methylation was not correlated with sex, cirrhosis, tumor differentiation, clinical stage. No association was found between p16 methylation or alteration and the prognosis of patients with HCC in overall survival (OS) and disease-free survival (DFS). Although p16 expression was significantly correlated with a poor prognosis in OS and DFS (P < .05) Our results indicate that p16 methylation was linked to the development, age, HBV, and HCV infection of HCC. p16 methylation or alteration was not associated with the prognosis, but p16 expression was linked to a poor survival.

Expression of hypoxia-inducible factors (HIFs) has been observed, but their prognostic role in advanced cancers remains uncertain. We conducted a meta-analysis to establish the prognostic effect of HIFs and to better guide treatment planning for advanced cancers. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was also performed. The clinical outcomes included overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), relapse/recurrence-free survival (RFS), and metastasis-free survival (MFS) in patients with advanced tumors according to multivariate analysis. A total of 31 studies including 3453 cases who received chemotherapy, radiotherapy, or chemoradiotherapy were identified. Pooled analyses revealed that HIF-1α expression was correlated with worse OS (HR = 1.61, p < 0.001), DFS (HR = 1.61, p < 0.001), PFS (HR = 1.49, p = 0.01), CSS (HR = 1.65, p = 0.056), RFS (HR = 2.10, p = 0.015), or MFS (HR = 2.36, p = 0.002) in advanced cancers. HIF-1α expression was linked to shorter OS in the digestive tract, epithelial ovarian, breast, non-small cell lung, and clear cell renal cell carcinomas. Subgroup analysis by study region showed that HIF-1α expression was correlated with poor OS in Europeans and Asians, while an analysis by histologic subtypes found that HIF-1α expression was not associated with OS in squamous cell carcinoma. No relationship was found between HIF-2α expression and OS, DFS, PFS, or CSS. Targeting HIF-1α may be a useful therapeutic approach to improve survival for advanced cancer patients. Based on TSA, more randomized controlled trials are strongly suggested.

Objective: Cancer stem cell marker CD44 and its variant isoforms (CD44v) may be correlated with tumor growth, metastasis and chemo-radiotherapy resistance. However, the prognostic power of CD44 and CD44v in advanced cancer remains controversial. Therefore, the purpose of our study was to generalize the prognostic significance of these cancer stem cell markers in advanced cancer patients. Methods: Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated from multivariable analysis to assess the associations among CD44, CD44v6, and CD44v9 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Trial sequential analysis (TSA) was also conducted. Results: We included 15 articles that reported on 1,201 patients with advanced cancer (CD44: nine studies with 796 cases, CD44v6: three studies with 143 cases, and CD44v9: three studies with 262 cases). CD44 expression was slightly linked to worse OS (HR = 2.03, P = 0.027), but there was no correlation between CD44 expression and DFS, RFS, or PFS. Stratified analysis showed that CD44 expression was not correlated with OS at ≥ 5 years or OS in patients receiving adjuvant therapy. CD44v6 expression was not associated with OS. CD44v9 expression was closely associated with poor 5-year CSS in patients treated with chemo/radiotherapy (HR = 3.62, P < 0.001). However, TSA suggested that additional trials were needed to confirm these conclusions. Conclusions: CD44 or CD44v9 might be novel therapeutic targets for improving the treatment of advanced cancer patients. Additional prospective clinical trials are strongly needed across different cancer types.