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Objective: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development., Design: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies., Results: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10 - 8  and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1 , resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L , while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10 - 9 ) and 4q28.1 (OR=1.14, p=3.33×10 - 11 ) were associated with GC risk., Conclusion: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations., Methods: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up., Findings: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10 -8 , including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; p trend =2·02 × 10 -9 ). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years., Interpretation: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations., Funding: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The association of ABO blood groups with gastric cancer risk was proposed decades ago, but the results have been inconsistent., Methods: We used two single nucleotide polymorphisms to determine ABO genotype in 4932 gastric cancer cases and 6158 controls of Chinese descent, and evaluated the associations of ABO blood groups and genotypes with risk of gastric cancer using multivariable logistic regression models. We also systematically reviewed published literature and performed a meta-analysis of all relevant studies., Results: In the case-control study, compared with blood group O, both blood group A and AB were associated with increased gastric cancer risk (for group A, odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.02-1.24; for group AB, OR = 1.18, 95% CI: 1.02-1.36, respectively). Analyses of ABO genotypes revealed associations of AO and AB with risk of gastric cancer compared with OO genotype. Consistent with the case-control study, meta-analysis of 40 studies including 33,613 cases and 2,431,327 controls demonstrated that blood group A (OR = 1.19, 95% CI: 1.13-1.25) and AB (OR = 1.09, 95% CI: 1.03-1.16) were associated with increased risk of gastric cancer., Conclusions: Our analyses validated the association of blood group A with risk of gastric cancer, and suggested that blood group AB was also associated with gastric cancer risk. Functional investigations are warranted to elucidate the exact mechanism of ABO blood groups in gastric carcinogenesis.

Many features are shared between esophageal cancer (EC) and gastric cancer (GC). This study aimed to explore whether known EC susceptibility loci are also important in the development of GC. A total of 21 genetic variants associated with EC in genome-wide association studies were evaluated with association of GC risk in 2631 cases and 4373 controls of Chinese ancestry. Single variant and weighted genetic scores (WGS) for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and overall EC were analyzed with GC risk, respectively. Genetic variants of rs2274223 in PLCE1 at 10q23.33 (per G allele: odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.16-1.38, P = 6.51 × 10 -8 ), rs10052657 in PDE4D at 5q11.2 (per C allele: OR = 1.12, 95% CI: 1.01-1.25, P = 3.28 × 10 -2 ) and rs671 in ALDH2 at 12q24.12 (per A-allele: OR = 0.83, 95% CI: 0.75-0.91, P = 1.14 × 10 -4 ) were significantly associated with GC risk. The combined effect of those three variants had stronger influence on GC risk (OR = 1.31, 95% CI: 1.19-1.44, P = 2.34 × 10 -8 ). High WGS of ESCC was also associated with increased risk of GC (P = 5.52 × 10 -4 as a continuous variable) (trend test P = 2.71 × 10 -4 ), whereas no statistically significant associations were observed between the WGS of EAC and GC risk (P = 0.66 as a continuous variable) (trend test P = 0.70). ESCC rather than EAC may share genetic susceptibility with GC. Genetic variants at 10q23.33, 5q11.2, and 12q24.12 may be useful as biomarkers to identify individuals with high risk for both ESCC and GC.

Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population. Three tagging SNPs in PPP2CA were genotyped using Illumina Human Exome BeadChip. We observed that the A allele of rs13187105 was associated with an increased risk of gastric cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.02-1.28, P = 0.017). Further analyses showed that rs13187105 [A] was associated with decreased expression of PPP2CA mRNA (P = 5.1 × 10 -6 ), and PPP2CA mRNA was significantly lower in gastric tumor tissues when comparing that in their adjacent normal tissues (P = 0.037). These findings support our hypothesis that genetic variants in PPP2CA may be implicated in gastric cancer susceptibility in Chinese population.