Background:Circulating microRNAs (miRNAs) have been implicated as novel biomarkers for gastric cancer (GC) diagnosis. However, the mixture of GC subtypes may have led to the inconsistent circulating miRNA profiles, and the clinical performance of circulating miRNAs has not yet been evaluated independently on early detection of GC.Methods:A four-phase study was designed with a total of 160 cancer-free controls, 124 patients with gastric non-cardia adenocarcinoma (GNCA) and 36 patients diagnosed gastric cardia adenocarcinoma (GCA). In the discovery phase, we screened the miRNA expression profile in plasma of 40 GNCA patients (stage I) and 40 matched controls by TaqMan low density array (TLDA) chips with pooled samples. Differentially expressed miRNAs were further validated in individual sample using quantitative reverse-transcriptase PCR (qRT–PCR) in the training phase. Subsequently, in an independent validation phase, the identified miRNAs were evaluated in 48 GNCA patients (stage I) and 102 matched controls. Finally, the identified miRNAs were further assessed in an external validation phase including advanced GNCA and GCA patients. Additionally, the expression levels of identified miRNAs were measured in the media of BGC823 and MGC803 cell lines.Results:Five miRNAs (miR-16, miR-25, miR-92a, miR-451 and miR-486-5p) showed consistently elevated levels in plasma of the GC patients as compared with controls, and were identified to be potential markers for GNCA with area under the receiver operating characteristic (ROC) curves (AUCs) ranging from 0.850 to 0.925 and 0.694 to 0.790 in the training and validation phases, respectively. The five-miRNA panel presented a high diagnostic accuracy for the early-stage GNCA (AUCs=0.989 and 0.812 for the training and validation phases, respectively). Three miRNAs (miR-16, miR-25 and miR-92a) were excreted into the culture media of GC cell lines.Conclusions:The five-miRNA panel in plasma may serve as a potential non-invasive biomarker in detecting the early-stage GC.

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. A series of epidemiological studies have examined the association between telomere length and the risk of cancers, but the findings remain conflicting. We performed literature review and meta-analysis to demonstrate the relationship between telomere length and cancer risk. A total of 23,379 cases and 68,792 controls from 51 publications with 62 population studies were included in this meta-analysis to assess the association between overall cancer or cancer-specific risk and telomere length. General association and dose-response relationship were evaluated based on two and three groups, respectively. The estimates of association were evaluated with odds ratios and 95% confidence intervals by the random-effects or fixed-effects model based on heterogeneity test. We observed a non-significant association between short telomeres and overall risk of cancer. Convincing evidence was observed for the association of short telomeres with an increased risk of gastrointestinal tumor and head and neck cancer. Significant dose-response associations were also observed for gastrointestinal tumor and head and neck cancer. Our findings indicate that telomeres may play diverse roles in different cancers, and short telomeres may be risk factors for the tumors of digestive system.

The familial aggregation indicated the inheritance of cancer risk. Recent genome-wide association studies (GWAS) have identified a number of common single nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome-wide complex trait analysis (GCTA) for common cancers at nine anatomical sites in Chinese population (14,629 cancer cases vs. 17,554 controls) and estimated the heritability of these cancers based on the common SNPs. We found that common SNPs explained certain amount of heritability with significance for all nine cancer sites: gastric cancer (20.26%), esophageal squamous cell carcinoma (19.86%), colorectal cancer (16.30%), lung cancer (15.17%), and epithelial ovarian cancer (13.31%), and a similar heritability around 10% for Hepatitis B virus (HBV)-related hepatocellular carcinoma, prostate cancer, breast cancer and nasopharyngeal carcinoma. We found that nearly or less than 25% change was shown when removing the regions expanding 250kb or 500kb up and downwards of the GWAS-reported SNPs. We also found strong linear correlations between variance partitioned by each chromosome and chromosomal length only for lung cancer (R2=0.641, P=0.001) and esophageal squamous cell cancer (R2=0.633, P=0.002), which implied us the complex heterogeneity of cancers. These results indicate polygenic genetic architecture of the nine common cancers in Chinese population. Further efforts should be made to discover the hidden heritability of different cancer types among Chinese.

Objective Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. Design We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. Results The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 ( per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10 −11 ). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (P wilcoxon signed-rank =7.20×10 −4). We also identified a new signal at the 1q22 locus, rs80142782 ( per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10 ), which was independent of the previously reported SNP at the same locus, rs4072037 ( per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10 −17 ). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (P conditional =3.47×10 −8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. Conclusion These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.

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.