Long non-coding RNA NRAV in the 12q24.31 risk locus drives gastric cancer development through glucose metabolism reprogramming.

Long non-coding RNAs (lncRNAs) serve as vital candidates to mediate cancer risk. Here, we aimed to identify the risk single-nucleotide polymorphisms (SNPs)-induced lncRNAs and to investigate their roles in gastric cancer (GC) development. Through integrating the differential expression analysis of lncRNAs in GC tissues and expression quantitative trait loci analysis in normal stomach tissues and GC tissues, as well as genetic association analysis based on GC genome-wide association studies and an independent validation study, we identified four lncRNA-related SNPs consistently associated with GC risk, including SNHG7 [odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.09-1.23], NRAV (OR = 1.11, 95% CI: 1.05-1.17), LINC01082 (OR = 1.16, 95% CI: 1.08-1.22) and FENDRR (OR = 1.16, 95% CI: 1.07-1.25). We further found that a functional SNP rs6489786 at 12q24.31 increases binding of MEOX1 or MEOX2 at a distal enhancer and results in up-regulation of NRAV. The functional assays revealed that NRAV accelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically, NRAV decreases the expression of key subunit genes through the electron transport chain, thereby driving the glucose metabolism reprogramming from aerobic respiration to glycolysis. These findings suggest that regulating lncRNA expression is a crucial mechanism for risk-associated variants in promoting GC development.

Development, validation, and evaluation of a risk assessment tool for personalized screening of gastric cancer in Chinese populations.

BACKGROUND: Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. METHODS: In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40-75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20-80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. RESULTS: The GCRS using 11 questionnaire-based variables demonstrated a Harrell's C-index of 0.754 (95% CI, 0.745-0.762) and 0.736 (95% CI, 0.710-0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. CONCLUSIONS: The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Genetic variants associated with expression of TCF19 contribute to the risk of head and neck cancer in Chinese population.

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified. METHODS: An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN. RESULTS: We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45×10-7 for rs2517611 at 6p22.1, p=1.76×10-9 for rs2524182 at 6p21.33 and p=2.17×10-10 for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify TCF19 expression by regulating the binding affinity of the transcription factor SREBF1 to the promoter of TCF19. In addition, experiments revealed that the inhibition of TCF19 may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN. CONCLUSION: These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that TCF19 may function as a putative susceptibility gene for SCCHN.

Prevalence of Helicobacter pylori infection in China: A systematic review and meta-analysis.

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection rates have been changing with different populations and geographic areas. We systematically evaluated the longitudinal trends in H. pylori prevalence in China over the past decades. METHODS: We performed a systematic review of literature reporting the prevalence of H. pylori infection in mainland China from 1990 to 2019 in the PubMed and China National Knowledge Infrastructure databases. We conducted a meta-analysis of qualified studies using a random effects model to estimate the pooled prevalence with a 95% confidence interval (95%CI). RESULTS: A total of 412 eligible studies with 1 377 349 subjects were included. The pooled H. pylori prevalence was 44.2% (95%CI: 43.0-45.5%) in mainland China, with an estimated 589 million individuals infected with H. pylori. The prevalence was relatively high in the Northwest (51.8%, 95%CI: 47.5-56.1%), East (47.7%, 95%CI: 45.4-50.0%), and Southwest China (46.6%, 95%CI: 42.1-51.1%). The prevalence significantly decreased from 58.3% (95%CI: 50.7-65.5%) in the period 1983-1994 to 40.0% (95%CI: 38.2-41.8%) in the period 2015-2019. The prevalence increased with age, ranging from 28.0% (95%CI: 23.9-32.5%) in children and adolescents to 46.1% (95%CI: 44.5-47.6%) in adults. CONCLUSION: Although the burden of H. pylori infections is still huge in China, the infection rate has been decreasing over the past decades. Targeted H. pylori eradication strategies may be considered in areas or populations with a high incidence of gastric cancer.

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations.

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.

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.

Functional genetic variants in centrosome-related genes CEP72 and YWHAG confer susceptibility to gastric cancer.

Structural and numeric centrosome aberrations can induce chromosome segregation errors and promote tumor development and progression. We systematically evaluated associations of 19,603 single nucleotide polymorphisms (SNPs) across 136 centrosome-related genes with gastric cancer (GC) risk using four GWAS datasets with a total of 3771 cases and 5426 controls. We identified two loci at 15p13.3 and 7q11.23 significantly associated with GC risk, whose risk alleles were correlated with increased mRNA expression of CEP72 (P = 7.30 × 10-4) and YWHAG (P = 1.60 × 10-3), respectively. Dual-luciferase reporter assays confirmed that the risk T allele of rs924607 at 15p13.3 significantly increased a promoter activity of the reporter gene, leading to a higher CEP72 expression level. At 7q11.23, the risk haplotype of rs2961037 [G]-rs2961038 [G] significantly elevated an enhancer activity and the expression of YWHAG. Both the mRNA and protein levels of CEP72 and YWHAG were overexpressed in GC tumor tissues compared with peritumor tissues and overexpression of either gene showed an unfavorable prognosis of GC patients. Moreover, knockdown of either CEP72 or YWHAG inhibited GC cell proliferation, migration and invasion and promoted GC cell apoptosis. The genes coexpressed with CEP72 or YWHAG in GC tumor tissues were enriched in the Ras signaling pathway, which was confirmed that knockdown of either one decreased the expression of cyclin D1 but increased the expression of p21 and p27. In conclusion, genetic variants at 15p13.3 and 7q11.23 may confer GC risk via modulating the biological functions of CEP72 and YWHAG, respectively, suggesting the importance of centrosome-regulated genes in GC development.

Hypomethylation-activated cancer-testis gene SPANXC promotes cell metastasis in lung adenocarcinoma.

Many studies have shown that there were similarity between tumorigenesis and gametogenesis. Our previous work found that cancer-testis (CT) genes could serve as a novel source of candidate of cancer. Here, by analysing The Cancer Genome Atlas (TCGA) database, we characterized a CT gene, SPANXC, which is expressed only in testis. The SPANXC was reactivated in lung adenocarcinoma (LUAD) tissues. And the expression of SPANXC was associated with prognosis of LUAD. We also found that the activation of SPANXC was due to the promoter hypomethylation of SPANXC. Moreover, SPANXC could modulate cell metastasis both in vitro and in vivo. Mechanistically, we found that SPANXC could bind to ROCK1, a metastasis-related gene, and thus SPANXC may regulate cell metastasis partly through interaction with ROCK1 in LUAD. Together, our results demonstrated that the CT expression pattern of SPANXC served as a crucial role in metastasis of LUAD. And these data further corroborated the resemblance between processes of germ cell development and tumorigenesis, including migration and invasion.

Multi-marker analysis of genomic annotation on gastric cancer GWAS data from Chinese populations.

BACKGROUND: Gastric cancer (GC) is one of the high-incidence and high-mortality cancers all over the world. Though genome-wide association studies (GWASs) have found some genetic loci related to GC, they could only explain a small fraction of the potential pathogenesis for GC. METHODS: We used multi-marker analysis of genomic annotation (MAGMA) to analyze pathways from four public pathway databases based on Chinese GWAS data including 2631 GC cases and 4373 controls. The differential expressions of selected genes in certain pathways were assessed on the basis of The Cancer Genome Atlas database. Immunohistochemistry was also conducted on 55 GC and paired normal tissues of Chinese patients to localize the expression of genes and further validate the differential expression. RESULTS: We identified three pathways including chemokine signaling pathway, potassium ion import pathway, and interleukin-7 (IL7) pathway, all of which were associated with GC risk. NMI in IL7 pathway and RAC1 in chemokine signaling pathway might be two new candidate genes involved in GC pathogenesis. Additionally, NMI and RAC1 were overexpressed in GC tissues than normal tissues. CONCLUSION: Immune and inflammatory associated processes and potassium transporting might participate in the development of GC. Besides, NMI and RAC1 might represent two new key genes related to GC. Our findings might give new insight into the biological mechanism and immunotherapy for GC.

Exome Array Analysis Identifies Variants in SPOCD1 and BTN3A2 That Affect Risk for Gastric Cancer.

BACKGROUND & AIMS: Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric cancer. We aimed to identify low-frequency and other genetic variants that determine gastric cancer susceptibility. METHODS: We performed exome array analysis of DNA in blood samples from 1113 patients with gastric cancer, collected at hospitals from 2006 to 2010 in China, and 1848 individuals without cancer (controls) undergoing physical examinations. Among 71,290 variants analyzed (including 25,784 common variants), 24 variants were selected and replicated in an analysis of DNA in blood samples from 4687 additional cases of gastric cancer and 5780 controls. We compared expression of candidate genes in tumor vs normal gastric tissues using data from TCGA and performed functional annotation analyses. An immortalized human gastric epithelial cell line (GES1) and 7 human gastric cancer lines were used to express transgenes, knock down gene expression (with small interfering RNAs), disrupt genes (using the CRISPR/Cas9 system), or assess expression of reporter constructs. We measured cell proliferation, colony formation, invasion, and migration, and assessed growth of xenograft tumors in nude mice. RESULTS: A low-frequency missense variant rs112754928 in the SPOC domain containing 1 gene (SPOCD1; encoding p.Arg71Trp), at 1p35.2, was reproducibly associated with reduced risk of gastric cancer (odds ratio, 0.56; P = 3.48 × 10-8). SPOCD1 was overexpressed in gastric tumors, and knockout of SPOCD1 reduced gastric cancer cell proliferation, invasive activity, and migration, as well as growth of xenograft tumors in nude mice. We also associated the variant rs1679709 at 6p22.1 with reduced risk for gastric cancer (odds ratio, 0.80; P = 1.17 × 10-13). The protective allele rs1679709-A correlated with the surrounding haplotype rs2799077-T-rs2799079-C, which reduced the enhancer activity of this site to decrease expression of the butyrophilin subfamily 3 member A2 gene (BTN3A2). BTN3A2 is overexpressed in gastric tumors, and deletion of BTN3A2 inhibited proliferation, migration, and invasion of gastric cancer cells. CONCLUSIONS: We have associated variants at 1p35.2 and 6p22.1 with gastric cancer risk, indicating a role for SPOCD1 and BTN3A2 in gastric carcinogenesis.

Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies.

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 (Pwilcoxon 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=1.71×10-19), 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 (Pconditional=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.

Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population.

Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.84 (95% confidence interval, 0.77-0.91; P = 2.95 × 10-5 ). The rs7023329-G allele was related to a high expression of MTAP (P = 0.020). The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele odds ratio of 1.12 (95% confidence interval, 1.01-1.24; P = 0.039). We also found that the carriers of the risk allele rs1679013-C had lower expression of CDKN2B than non-carriers (P = 0.035). CDKN2B was also significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues (P = 3.50×10-5 ). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of the 9p21.3 locus in cancer development.

High mitochondrial DNA copy number was associated with an increased gastric cancer risk in a Chinese population.

Mitochondrial DNA (mtDNA) copy number (mtCN) may be a potential biomarker in relation to cancer risk. However, the role of mtCN in gastric cancer remains uncertain. We examined the association between peripheral blood leukocytes mtCN level and gastric cancer risk in a case-control study including 984 gastric cancer cases and 984 controls. We measured relative mtCN level by real-time quantitative PCR-based assay, and used logistic regression models to assess the association between mtCN and risk of gastric cancer. The mtCN level in gastric cancer cases was significantly higher than that in controls (median value: 6.53 vs 4.12, P = 1.79 × 10-5 ). Compared with those with low mtCN, the risk for gastric cancer was 1.29 (95% confidence interval [CI] = 1.02-1.63) in the median group and 1.74 (95%CI = 1.39-2.18) in the high mtCN group (P for trend = 1.51 × 10-6 ). Because relative telomere length (RTL) has been associated with gastric cancer risk in our previous study, we also evaluated the combined effects of mtCN and RTL on gastric cancer risk. Multivariable regression model revealed that the effects of mtCN and RTL were independent on gastric cancer risk. Compared with those in the lowest risk group by combining mtCN and RTL, the odds ratio for gastric cancer was 4.30 (95%CI = 2.79-6.63) in the highest risk group. Our results suggest that mtDNA may be implicated in gastric carcinogenesis and mtCN as well as RTL may serve as joint susceptible biomarkers for gastric cancer.

Genetic variants affecting telomere length are associated with the prognosis of esophageal squamous cell carcinoma in a Chinese population.

Telomeres are essential for maintaining chromosomal stability and are crucial in tumor progression. Previous studies have explored the associations between telomere length and cancer prognosis, but the findings are inconclusive. Genome-wide association studies have identified several genetic variants associated with telomere length in Caucasians. However, the roles of telomere length and related genetic variants on esophageal squamous cell carcinoma (ESCC) prognosis are largely unknown. Therefore, we conducted a case-cohort study with 431 ESCC patients to assess the associations between relative telomere length (RTL), eight known telomere length related variants and the overall survival of ESCC in Chinese population. We found that as compared with the reference group, patients in the fifth (the longest) quintile had a significantly better prognosis [(adjusted hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98, P = 0.041]. Furthermore, A allele of rs2736108 was significantly associated with both the increased RTL (P = 0.048) and the better prognosis of ESCC (adjusted HR = 0.55, 95%CI = 0.38-0.79, P = 1.31 × 10-3 ). Mediation analysis indicated that the effect of rs2736108 on ESCC prognosis was partly explained by RTL (1.99%). Stepwise Cox proportional hazard analysis suggested that rs2736108 played an important protective role in ESCC prognosis (HR = 0.57, 95%CI = 0.40-0.81, P = 1.97 × 10-3 ). Our findings provide evidence that prolonged telomere length is a protective factor for ESCC patients' survival and the known telomere length related genetic variant rs2736108 can contribute to the prognosis of ESCC as well in Chinese population. © 2016 Wiley Periodicals, Inc.

Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case-control study in the Chinese population.

BACKGROUND: The cysteinyl transfer RNA synthetase gene (CARS) is located on chromosome band 11p15.5, which is an important tumor-suppressor gene region. Mutations in CARS have been identified in many kinds of cancers; however, evidence for a relationship between genetic variants in CARS and gastric cancer at the population level is still lacking. Thus, we explored the association of variants in CARS with gastric cancer using a two-stage case-control strategy in Chinese. METHODS: We undertook a two-stage case-control study to investigate the association between polymorphisms in CARS and risk of gastric cancer with use of an Illumina Infinium® BeadChip and an ABI 7900 system. RESULTS: Four single nucleotide polymorphisms (SNPs) were significantly associated with gastric cancer risk in both the discovery stage and the validation stage after adjustment for age and sex. In addition, the combined results of the two stages showed these SNPs were related to gastric cancer risk (P false discovery rate ≤ 0.001 for rs384,490, rs729662, rs2071101, and rs7394702). In silico analyses revealed that rs384490 and rs7394702 could affect transcription factor response elements or DNA methylation of CARS, and rs729662 was associated with the prognosis of gastric cancer. Additionally, expression quantitative trait loci analysis showed rs384490 and rs729662 might alter expression of CARS-related genes. CONCLUSIONS: The potential functional SNPs in CARS might influence the biological functions of CARS or CARS-related genes and ultimately modify the occurrence and development of gastric cancer in Chinese. Further large-scale population-based studies or biological functional assays are warranted to validate our findings.

Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival.

The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression.

Type 2 diabetes, glycaemic traits and upper gastrointestinal cancer risk: a prospective cohort study.

BACKGROUND: Type 2 diabetes (T2D) has been linked with site-specific upper gastrointestinal (UGI) cancers during the past decades, but associations are still inconclusive. This study aimed to determine the association between T2D, glycaemic traits (random blood glucose and HbA1c) and UGI cancer (oesophageal and gastric cancer). METHODS: In the present study, based on the large-scale prospective cohort of UK Biobank, we included 452 631 eligible participants. T2D was defined according to baseline self-report data, clinical data and biochemistry data. Random blood glucose and HbA1c were measured at baseline. Polygenic risk score was used to classify individuals into different UGI cancer genetic risks. Multivariable Cox regression models were used to estimate HRs and 95% CIs. RESULTS: During a median follow-up of 10.26 years (IQR: 9.47-10.97), 1392 incident UGI cancer cases were identified. T2D was significantly associated with a 44% increment in UGI cancer risk (95% CI 1.22 to 1.70, p<0.001). Moreover, per SD increase in random blood glucose and HbA1c was associated with 7% (95% CI 1.03 to 1.12, p<0.001) and 6% (95% CI 1.04 to 1.09, p<0.001) increased hazards of developing UGI cancer, respectively. Patients with T2D at high genetic risk had a 2.33-fold hazard of UGI cancer (95% CI 1.66 to 3.28, p<0.001), compared with non-T2D individuals at low genetic risk. CONCLUSION: Our results indicate that T2D and elevated levels of glycaemic traits may be risk factors for incident UGI cancer. Individuals with a high genetic risk and T2D have a significantly increased risk of developing UGI cancer.

Associations of combined phenotypic aging and genetic risk with incident cancer: A prospective cohort study.

Background: Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer. Methods: Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs). Results: Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18-1.27) in men, and 1.26 (1.22-1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10-2.51) for men and 1.94 (1.78-2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = -1.01 in men, p<0.001; Beta = -0.98 in women, p<0.001). Conclusions: Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle. Funding: This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).

Age is a major risk factor for cancer. Other factors, such as lifestyle or environmental exposures, may increase or mitigate cancer risks. Biological age, which considers accelerated aging processes, may, however, better predict cancer risk than chronological age. Some scientists propose using biological aging measures as an alternative for assessing cancer and other age-related disease risks, as these markers may provide a more accurate assessment of the various factors contributing to cancer risk. PhenoAge, a measure of biological aging processes in the body, could provide an alternative way to assessing aging-related cancer risks. This tool utilizes an individual's chronological age and nine biomarkers of aging processes. It has the potential to identify individuals whose aging process is accelerated compared to their peers, potentially indicating an increased cancer risk. This information may empower them to make lifestyle changes that could significantly reduce their risk. To assess the suitability of PhenoAge, Bian, Ma et al. used nine clinical chemistry biomarkers and chronological age to calculate PhenoAge in 374,463 participants from the UK Biobank. Their findings revealed that people with older PhenoAges ­ regardless of their genetic risk profiles ­ have an increased risk of cancer. Individuals with higher PhenoAge scores, indicating accelerated biological aging, had a roughly 25 percent higher risk of developing cancer. Individuals with both a high genetic risk and higher PhenoAge score had roughly double the risk of cancer. People with lower PhenoAges were more likely to have healthier lifestyles. These results suggest that adopting healthier lifestyles may slow the aging process and reduce cancer risk. While the analyses conducted by Bian, Ma et al. provide promising insights, they also underscore the need for further research. PhenoAge may offer a way to assess biological aging and identify individuals at higher risk of cancer. Those with higher PhenoAge scores may benefit from earlier cancer screening, and adopting a healthier lifestyle could potentially slow down the aging process and reduce their cancer risk. However, more studies in more diverse cohorts of people are needed to confirm that PhenoAge is a reliable marker for cancer risk and to test interventions to slow aging and reduce cancer risks in individuals with accelerated aging.

Comprehensive functional interrogation of susceptibility loci in GWASs identified KIAA0391 as a novel oncogenic driver via regulating pyroptosis in NSCLC.

Approximately 51 non-small-cell lung cancer (NSCLC) risk loci have been identified by genome-wide association studies (GWASs). We conducted a high throughput RNA-interference (RNAi) screening to identify the candidate causal genes in NSCLC risk loci. KIAA0391 at 14q13.1 had the highest score and could promote proliferation and metastasis of NSCLC in vitro and in vivo. We next prioritized rs3783313 as a causal variant at 14q13.1, by integrating a large-scale population study consisting of 27,120 lung cancer cases and 27,355 controls, functional annotation, and expression quantitative trait locus (eQTL) analysis. Then we found that rs3783313 could facilitate a promoter-enhancer interaction to upregulate KIAA0391 expression by affecting the affinity of transcription factor NFYA. Mechanistically, KIAA0391 knockdown dramatically influenced pyroptosis-related pathways and increased the expression of CASP1. And KIAA0391 transcriptionally repressed CASP1 by binding to SMAD2 and induced an anti-pyroptosis phenotype, promoting tumorigenesis of NSCLC, which provides new insights and potential target for NSCLC.