Background-Genetic variation plays an important role in the development of non-small cell lung cancer (NSCLC). However, major genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which deters us from using a polygenic risk score (PRS) to identify sub-populations at high-risk of lung cancer for prevention.Methods-To systematically identify genetic variants for NSCLC risk, we newly genotyped 19,546 samples and conducted a meta-analysis of genome-wide association studies (GWASs) of Dai et al.

Emerging evidence indicates that circular RNAs (circRNAs) are implicated in cancer development. This study aimed to evaluate whether circulating circRNAs may serve as novel biomarkers for non‐small cell lung cancer (NSCLC). We used RNA sequencing (RNA‐seq) and quantitative real‐time PCR to explore cancer‐related circRNAs. Bioinformatics and functional analyses were performed to reveal biological effects of circRNAs on lung cancer cells. A total of 5471 distinct circRNAs were identified by total RNA‐seq, in which 185 were differentially expressed between cancerous and adjacent normal tissues. A circRNA derived from exon 5–7 of the FARSA gene, termed circFARSA, was observed to increase in cancerous tissues (P = 0.016), and was more abundant in patients’ plasma than controls (P < 0.001). Overexpression of circFARSA in A549 cell line significantly promoted cell migration and invasion. In silico analysis suggested that circFARSA might sponge miR‐330‐5p and miR‐326, thereby relieving their inhibitory effects on oncogene fatty acid synthase. Summarily, this study revealed circRNA profile of NSCLC for the first time and provided the evidence of plasma circFARSA as a potential noninvasive biomarker for this malignancy.

Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P = 9.37 × 10−5). TCGA data confirm that the infiltrating B lymphocyte abundance is significantly higher in the EGFR-mutated patients (P = 0.007). Additionally, MS3-high patients carry a higher contribution of distant chromosomal rearrangements >1 Mb (P = 1.35 × 10−7), some of which result in fusions involving genes with important functions (i.e., ALK and RET). Thus, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers.

Three genome-wide association studies (GWAS) have been conducted on the genetic susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), two of which consistently identified tagging single nucleotide polymorphisms (SNPs) around HLA-DQ/DR. In contrast, large multi-centre association studies between HBV genotype, mutations and the risk of HCC are relatively rare, and their interactions with host variants are even less. We performed a multi-centre study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls to evaluate the effects of HBV genotype, mutations, GWAS-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) and their interactions on HCC risk. We found HBV genotype C was more frequent in HBV-related HCC. And 11 HBV hotspot mutations were independently and significantly associated with HCC risk. We also detected significant interactions of rs9272105 with both the HBV genotype and mutations. Through stepwise regression analysis, HBV genotype, the 11 mutations, HLA-DQ/DR SNPs, and the interaction of rs9272105 with mutation A1752G were all entered into the HCC prediction model, and the area under the curve for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840. The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers.

Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA) cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM) in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51-like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1α, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2α, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1α and HIF-2α expressions and thereby regulating AMPK/mTOR signaling pathway.

Background Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs). Methods Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St. Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine’s clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically-assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were two-sided. Results EAA was statistically significantly higher in survivors than controls (ALSM=0.63, 95%CI=0.26-1.01 vs. -3.61, 95%CI=-4.43-2.80). In a multivariable model among survivors, statistically significantly higher EAA (P&lt;0.05) was observed in those exposed to chest-radiotherapy (RT), abdomen/pelvic-RT, alkylating agents, glucocorticoids or epipodophyllotoxins. Compared to survivors with favorable health behaviors (0.26, 95%CI=-0.36-0.87), EAA was statistically significantly higher among survivors with intermediate (1.07, 95%CI=0.59-1.54) or unfavorable health behaviors (1.45, 95%CI=0.60-2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of seven CHCs: hypertension (3rd vs. 1st tertile, Relative Rate [RR]=1.83, 95%CI=1.17-2.83), myocardial infarction (RR = 2.91, 95%CI=1.27-7.21), obesity (RR = 1.39, 95%CI=1.17-1.66), obstructive pulmonary deficit (RR = 1.86, 95%CI=0.95-3.77), peripheral motor neuropathy (RR = 2.89, 95%CI=1.24-6.97), peripheral sensory neuropathy (RR = 2.04, 95%CI=0.99-4.26), and pulmonary diffusion deficits (RR = 2.75, 95%CI=0.95-7.63). Conclusions EAA is statistically significantly higher in survivors of childhood cancer than in non-cancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.

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The authors declare no potential conflicts of interest.