Lingjun Zhu

Genetic variants in lncRNA HOTAIR are associated with risk of colorectal cancer

Long non-coding RNA HOX transcript antisenseRNA (HOTAIR) has been widely identified to participate in tumour pathogenesis, acting as a promoter in colorectal cancer carcinogenesis. However, the association between genetic variants in HOTAIR and cancer risk has not yet been reported. In the present study, we performed a two-stage case-control study to investigate the association between HOTAIR tagSNPs and the risk of colorectal cancer. We found that individuals with rs7958904 CC genotype had a significantly decreased risk of colorectal cancer in both Stage 1 and 2, compared with those carrying GG genotype [odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.51-0.97 in Stage 1; OR = 0.58, 95% CI = 0.37-0.91 in Stage 2; OR = 0.67, 95% CI = 0.51-0.87 in combined stage]. The subsequently stratified analyses showed that the protective effect of rs7958904 was more pronounced in several subgroups. In summary, our study showed that genetic variants in HOTAIR were associated with risk of colorectal cancer and rs7958904 may act as a potential biomarker for predicting the risk of colorectal cancer.

A Functional Polymorphism in miRNA-196a2 Is Associated with Colorectal Cancer Risk in a Chinese Population

Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC.

Gefitinib or Erlotinib as Maintenance Therapy in Patients with Advanced Stage Non-Small Cell Lung Cancer: A Systematic Review

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib have been tested as maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC). The studies are quite heterogenous regarding study size and populations, and a synopsis of these data could give some more insight in the role of maintenance therapy with TKI. Methods In September 2012 we performed a search in the pubmed, EMBASE and Cochrane library databases for randomized phase III trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through a rigorous selection process with specific criteria, five trials (n = 2436 patients) were included for analysis. Standard statistical methods for meta-analysis were applied. Results TKIs (gefitinib and erlotinib) significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50–0.76, I2 = 78.1%] and overall survival (HR 0.84, 95% CI 0.76–0.93, I2 = 0.0%) compared with placebo or observation. The PFS benefit was consistent in all subgroups including stage, sex, ethnicity, performance status, smoking status, histology, EGFR mutation status, and previous response to chemotherapy. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit. Overall survival benefit was observed in patients with clinical features such as female, non-smoker, smoker, adenocarcinoma, and previous stable to induction chemotherapy. Severe adverse events were not frequent. Main limitations of this analysis are that it is not based on individual patient data, and not all studies provided detailed subgroups analysis. Conclusions The results show that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. Given the less toxicity of TKIs than chemotherapy and simple oral administration, this treatment strategy seems to be of important clinical value.

Genome-wide analysis of long noncoding RNA signature in human colorectal cancer.

Long noncoding RNAs (lncRNAs) have been widely regarded as crucial regulators in various biological processes involved in carcinogenesis. However, the comprehensive lncRNA expression signature in colorectal cancer remains fully unknown. We performed a high throughput microarray assay to detect lncRNA expression profile in three paired human colorectal cancer tissues and their adjacent normal tissues. Additional 90 paired colorectal samples were collected to verify differently expression levels of two selected lncRNAs using q-RT-PCR assay. Bioinformatic approaches were performed to explore into the functions of these differently expressed lncRNAs. Microarray assay showed a series of lncRNAs were differently expressed in colorectal cancer. Two of the lncRNAs, HOTAIR and a novel lncRNA, lncRNA-422 were confirmed in more samples (P=0.015 for HOTAIR and P=0.027 for lncRNA-422, respectively). GSEA indicated that gene sets most correlated with them were those named up-regulated in KRAS-over, down-regulated in JAK2-knockout, down-regulated in PDGF-over and down-regulated in TBK1-knockout, all of which were cancer-related. Subsequently, GO analyses of most significantly correlated coding genes of HOTAIR and lncRNA-422 showed that these two lncRNAs may participate in carcinogenesis by regulating protein coding genes involved in special biological process relevant to cancer. Our study demonstrated that different lncRNA expression patterns were involved in colorectal cancer. Besides, HOTAIR and lncRNA-422 were identified to participate in colorectal cancer. Further studies into biological mechanisms of differently expressed lncRNAs identified in our study will help to provide new perspective in colorectal cancer pathogenesis.

Clinical potential role of circulating microRNAs in early diagnosis of colorectal cancer patients

Current procedures for diagnosis and biomarker examination of colorectal cancer (CRC) are invasive and unpleasant. There is a great need to identify sensitive and specific biomarkers for early diagnosis of CRC. Circulating microRNAs (miRNAs) are promising molecular markers for CRC prediction. We performed a comprehensive meta-analysis to integrate an evaluation index for diagnostic accuracy of circulating miRNAs in diagnosing CRC patients. Furthermore, we conducted an independent validation set of 49 CRC patients and 49 healthy controls. In our meta-analysis, we found that miR-21 yielded a pooled area under ROC curve (AUC) of 0.867 (sensitivity: 76%, specificity: 82%) in discriminating CRC from controls, and miR-92a yielded a summary AUC of 0.803 (sensitivity: 77%, specificity: 68%); miR-21 had a higher diagnostic efficiency than miR-92a. In the further validation, plasma miR-21 levels in CRC patients were significantly higher than levels observed in healthy subjects. A ROC curve analysis showed a consistent result. However, this phenotype was not present in miR-92a. Moreover, the expression trend of miR-21 in plasma samples was in line with that of tissue samples, along with the cellular level. Current evidences suggest that plasma miR-21 could be a reliable and non-invasive biomarker for CRC diagnosis. Studies with larger cohorts that include the diagnostic value of plasma miR-21 for CRC are warranted.

Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials

Numerous studies have investigated the effects of folic acid supplementation on colorectal cancer risk, but conflicting results were reported. We herein performed a meta-analysis based on relevant studies to reach a more definitive conclusion. The PubMed and Embase databases were searched for quality randomized controlled trials (RCTs) published before October 2014. Eight articles met the inclusion criteria and were subsequently analyzed. The results suggested that folic acid treatment was not associated with colorectal cancer risk in the total population (relative risk [RR] = 1.00, 95% confidence interval [CI] = 0.82–1.22, P = 0.974). Moreover, no statistical effect was identified in further subgroup analyses stratified by ethnicity, gender, body mass index (BMI) and potential confounding factors. No significant heterogeneity or publication bias was observed. In conclusion, our meta-analysis demonstrated that folic acid supplementation had no effect on colorectal cancer risk. However, this finding must be validated by further large studies.

Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population

Objective The long non-coding RNA (lncRNA) gene, H19, has been involving in multiple biological functions, which also plays a vital role in colorectal cancer carcinogenesis. However, the association between genetic variants in H19 and colorectal cancer susceptibility has not been reported. In this study, we aim to explore whether H19 polymorphisms are related to the susceptibility of colorectal cancer. Methods We conducted a case-control study to evaluate the association between four selected single nucleotide polymorphisms (SNPs) (rs2839698, rs3024270, rs217727, and rs2735971) in H19 and the risk of colorectal cancer in a Chinese population. Results We found that individuals with rs2839698 A allele had a significantly increased risk of colorectal cancer, compared to those carrying G allele [odds ratio (OR) = 1.20, 95% confidence interval (CI) = 1.05–1.36 in additive model]. Further stratified analyses revealed that colon tumor site, well differentiated grade and Dukes stage of C/D were significantly associated with colorectal cancer risk (P < 0.05). Additionally, bioinformatic analysis showed that rs2839698 may change the crucial folding structures and alter the target microRNAs of H19. Conclusions Our results provided the evidence that rs2839698 in H19 was associated with elevated risk of colorectal cancer, which may be a potential biomarker for predicting colorectal cancer susceptibility.

Common genetic variation in ETV6 is associated with colorectal cancer susceptibility

Genome-wide association studies (GWASs) have identified multiple susceptibility loci for colorectal cancer, but much of heritability remains unexplained. To identify additional susceptibility loci for colorectal cancer, here we perform a GWAS in 1,023 cases and 1,306 controls and replicate the findings in seven independent samples from China, comprising 5,317 cases and 6,887 controls. We find a variant at 12p13.2 associated with colorectal cancer risk (rs2238126 in ETV6, P=2.67 × 10−10). We replicate this association in an additional 1,046 cases and 1,076 controls of European ancestry (P=0.034). The G allele of rs2238126 confers earlier age at onset of colorectal cancer (P=1.98 × 10−6) and reduces the binding affinity of transcriptional enhancer MAX. The mRNA level of ETV6 is significantly lower in colorectal tumours than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer.

Autologous cytokine-induced killer cell therapy in lung cancer patients: A retrospective study

Cytokine-induced killer (CIK) cells have the ability to kill tumor cells in vitro and in vivo. This study aimed to evaluate the clinical effect of adjuvant immunotherapy with CIK cells on the prognosis of lung cancer patients. In the present study, we investigated the clinical outcomes of autologous CIK cell immunotherapy for patients with lung cancer in a case-control study. Our study included 60 patients who received chemotherapy combined with autologous CIK cell adoptive immunotherapy in CIK treatment group and 60 patients who received chemotherapy alone in the control group. Progression-free survival (PFS) and overall survival (OS) of these two groups were evaluated. After 14 days of incubation in vitro, the percentages of CD3(+), CD3(+)CD8(+), CD3(+)CD56(+) and CD3(-)CD56(+) were significantly increased (P<0.05). The clinical symptoms of 60 patients were apparently improved. No severe toxicity and side effects were observed in the CIK treatment group. The 3-year, 5-year PFS rates were 44.7% and 26.8% and the 3-year, 5-year OS rates were 74% and 62% in the CIK group, respectively, which were significantly improved compared to that in the control group. The median PFS and OS in the CIK group were significantly improved than those in the control group (PFS, 24 months vs. 14 months, P=0.014; OS, 72 months vs. 44 months, P=0.006). Our results indicated that autologous CIK cells can efficiently improve the immunological status and prolong PFS and OS in patients with lung cancer.

Icotinib is an active treatment of non-small-cell lung cancer: a retrospective study.

Background Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small cell lung cancer (NSCLC). This retrospective analysis was performed to assess the efficacy of icotinib on patients with non-small-cell lung cancer (NSCLC). Methods 82 consecutive patients treated with icotinib as first (n = 24) or second/third line (n = 58) treatment at three hospitals in Nanjing were enrolled into our retrospective research. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the tumor responses and the progression-free survival (PFS) and overall survival (OS) was evaluated by the Kaplan-Meier method. Results Median PFS was 4.0 months (95% CI 2.311–5.689). Median OS was 11.0 months (95% CI 8.537–13.463) in this cohort. Median PFS for first and second/third line were 7.0 months (95% CI 2.151–11.8) and 3.0 months (95% CI 1.042–4.958), respectively. Median OS for first and second/third line were 13.0 months (95% CI 10.305–15.695) and 10.0 months (95% CI 7.295–12.70), respectively. In patients with EGFR mutation (n = 19), icotinib significantly reduced the risk of progression (HR 0.36, 95% CI 0.18–0.70, p = 0.003) and death (HR 0.10, 95% CI 0.02–0.42, p = 0.002) compared with those EGFR status unknown (n = 63). The most common adverse events were acne-like rash (39.0%) and diarrhea (20.7%). Conclusions Icotinib is active in the treatment of patients with NSCLC both in first or second/third line, especially in those patients harbouring EGFR mutations, with an acceptable adverse event profile.