Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer.

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82-0.93, p = 1.87 × 10-5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1-011. Transcript FARP1-011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk.

High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

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.

Family history and genetic risk score combined to guide cancer risk stratification: A prospective cohort study.

Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia.

Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA, GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1, GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10-9; rs1705003: OR = 2.37, p = 3.21 × 10-7), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5, GenBank: NC_000007.13:g.28848865G>T; ESYT3, GenBank: NC_000003.11:g.138183253C>T; and LPIN1, GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA.

Prenatal Parental Exposure to Metals and Birth Defects: A Prospective Birth Cohort Study.

While maternal exposure to high metal levels during pregnancy is an established risk factor for birth defects, the role of paternal exposure remains largely unknown. We aimed to assess the associations of prenatal paternal and maternal metal exposure and parental coexposure with birth defects in singletons. This study conducted within the Jiangsu Birth Cohort recruited couples in early pregnancy. We measured their urinary concentrations for 25 metals. A total of 1675 parent-offspring trios were included. The prevalence of any birth defects among infants by one year of age was 7.82%. Paternal-specific gravity-corrected urinary concentrations of titanium, vanadium, chromium, manganese, cobalt, nickel, copper, and selenium and maternal vanadium, chromium, nickel, copper, selenium, and antimony were associated with a 21-91% increased risk of birth defects after adjusting for covariates. These effects persisted after mutual adjustment for the spouse's exposure. Notably, when assessing the parental mixture effect by Bayesian kernel machine regression, paternal and maternal chromium exposure ranked the highest in relative importance. Parental coexposure to metal mixture showed a pronounced joint effect on the risk of overall birth defects, as well as for some specific subtypes. Our findings suggested a couple-based prevention strategy for metal exposure to reduce birth defects in offspring.

Associations of inflammation related prenatal adversities with neurodevelopment of offspring in one year: a longitudinal prospective birth cohort study.

BACKGROUND: The recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring. METHODS: Based on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring. RESULTS: Compared with "low IPAI" group, offspring with "high IPAI" have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted ß were - 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and - 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among "high IPAI" group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72). CONCLUSIONS: Our results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

Association of serum metal levels with type 2 diabetes: A prospective cohort and mediating effects of metabolites analysis in Chinese population.

Several studies have suggested an association between exposure to various metals and the onset of type 2 diabetes (T2D). However, the results vary across different studies. We aimed to investigate the associations between serum metal concentrations and the risk of developing T2D among 8734 participants using a prospective cohort study design. We utilized inductively coupled plasmamass spectrometry (ICP-MS) to assess the serum concentrations of 27 metals. Cox regression was applied to calculate the hazard ratios (HRs) for the associations between serum metal concentrations on the risk of developing T2D. Additionally, 196 incident T2D cases and 208 healthy control participants were randomly selected for serum metabolite measurement using an untargeted metabolomics approach to evaluate the mediating role of serum metabolite in the relationship between serum metal concentrations and the risk of developing T2D with a nested casecontrol study design. In the cohort study, after Bonferroni correction, the serum concentrations of zinc (Zn), mercury (Hg), and thallium (Tl) were positively associated with the risk of developing T2D, whereas the serum concentrations of manganese (Mn), molybdenum (Mo), barium (Ba), lutetium (Lu), and lead (Pb) were negatively associated with the risk of developing T2D. After adding these eight metals, the predictive ability increased significantly compared with that of the traditional clinical model (AUC: 0.791 vs. 0.772, P=8.85×10-5). In the nested casecontrol study, a machine learning analysis revealed that the serum concentrations of 14 out of 1579 detected metabolites were associated with the risk of developing T2D. According to generalized linear regression models, 7 of these metabolites were significantly associated with the serum concentrations of the identified metals. The mediation analysis showed that two metabolites (2-methyl-1,2-dihydrophthalazin-1-one and mestranol) mediated 46.81% and 58.70%, respectively, of the association between the serum Pb concentration and the risk of developing T2D. Our study suggested that serum Mn, Zn, Mo, Ba, Lu, Hg, Tl, and Pb were associated with T2D risk. Two metabolites mediated the associations between the serum Pb concentration and the risk of developing T2D.

Household air pollution and risk of incident lung cancer in urban China: A prospective cohort study.

Household air pollution (HAP) is associated with the development of lung cancer, yet few studies investigated the exposure patterns and joint associations with tobacco smoking. In our study, we included 224 189 urban participants from China Kadoorie Biobank (CKB), 3288 of which diagnosed with lung cancer during the follow-up. Exposure to four HAP sources (solid fuels for cooking/heating/stove and environmental tobacco smoke exposure) was assessed at baseline. Distinct HAP patterns and their associations with lung cancer were examined through latent class analysis (LCA) and multivariable Cox regression. A total of 76.1% of the participants reported regular cooking and 52.2% reported winter heating, of which 9% and 24.7% used solid fuels, respectively. Solid fuel heating increased lung cancer risk (Hazards ratio [HR]: 1.25, 95% confidence interval [CI]: 1.08-1.46). LCA identified three HAP patterns; the "clean fuel cooking and solid fuel heating" pattern significantly increased lung cancer risk (HR: 1.25, 95% CI: 1.10-1.41), compared to low HAP pattern. An additive interaction was observed between heavy smoking and "clean fuel cooking and solid fuel heating" (relative excess risk [RERI]: 1.32, 95% CI: 0.29-2.47, attributable proportion [AP]: 0.23, 95% CI: 0.06-0.36). Cases resulting from solid fuel account for ~4% of total cases (population attribute fraction [PAF]overall : 4.31%, 95% CI: 2.16%-6.47%, PAFever smokers : 4.38%, 95% CI: 1.54%-7.23%). Our results suggest that in urban China, solid fuel heating increased the risk of lung cancer, particularly among heavy smokers. The whole population could benefit from cleaner indoor air quality by reducing using solid fuels, especially smokers.

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (ßGTEx = 0.24, PGTEx = 9.81 × 10-15; ßNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (ßGTEx = -0.17, PGTEx = 2.82 × 10-8; ßNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.

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.

A two-stage genome-wide association study identified four potential early-onset nonsmall cell lung cancer risk loci based on 26,652 participants in Chinese population.

Early-onset lung cancer is rare with an increasing incidence rate. Although several genetic variants have been identified for it with candidate gene approaches, no genome-wide association study (GWAS) has been reported. In this study, a two-stage strategy was adopted: firstly we performed a GWAS to identify variants associated with early-onset nonsmall-cell lung cancer (NSCLC) risk using 2556 cases (age ≤ 50 years) and 13,327 controls by logistic regression model. To further discriminate younger cases from older ones, we took a case-case analysis for the promising variants with above early-onset cases and 10,769 cases (age > 50 years) by Cox regression model. After combining these results, we identified four early-onset NSCLC susceptibility loci at 5p15.33 (rs2853677, odds ratio [OR] = 1.48, 95% confidence interval [CI]: 1.36-1.60, Pcase-control = 3.58 × 10-21 ; hazard ratio [HR] = 1.10, 95% CI: 1.04-1.16, Pcase-case = 6.77 × 10-4 ), 5p15.1 (rs2055817, OR = 1.24, 95% CI: 1.15-1.35, Pcase-control = 1.39 × 10-7 ; HR = 1.08, 95% CI: 1.02-1.14, Pcase-case = 6.90 × 10-3 ), 6q24.2 (rs9403497, OR = 1.24, 95% CI: 1.15-1.35, Pcase-control = 1.61 × 10-7 ; HR = 1.11, 95% CI: 1.05-1.17, Pcase-case = 3.60 × 10-4 ) and 12q14.3 (rs4762093, OR = 1.31, 95% CI: 1.18-1.45, Pcase-control = 1.90 × 10-7 ; HR = 1.10, 95% CI: 1.03-1.18, Pcase-case = 7.49 × 10-3 ). Except for 5p15.33, other loci were found to be associated with NSCLC risk for the first time. All of them had stronger effects in younger patients than in older ones. These results provide a promising overview for early-onset NSCLC genetics.

Development and validation of a blood biomarker score for predicting mortality risk in the general population.

BACKGROUND: Blood biomarkers for multiple pathways, such as inflammatory response, lipid metabolism, and hormonal regulation, have been suggested to influence the risk of mortality. However, few studies have systematically evaluated the combined predictive ability of blood biomarkers for mortality risk. METHODS: We included 267,239 participants from the UK Biobank who had measurements of 28 blood biomarkers and were free of cardiovascular disease (CVD) and cancer at baseline (2006-2010). We developed sex-specific blood biomarker scores for predicting all-cause mortality risk in a training set of 247,503 participants from England and Wales, and validated the results in 19,736 participants from Scotland. Cox and LASSO regression analyses were performed to identify independent predictors for men and women separately. Discrimination and calibration were evaluated by C-index and calibration plots, respectively. We also assessed mediating effects of the biomarkers on the association between traditional risk factors (current smoking, obesity, physical inactivity, hypertension, diabetes) and mortality. RESULTS: A total of 13 independent predictive biomarkers for men and 17 for women were identified and included in the score development. Compared to the lowest tertile of the score, the highest tertile showed a hazard ratio of 5.36 (95% confidence interval [CI] 5.04-5.71) in men and 4.23 (95% CI 3.87-4.62) in women for all-cause mortality. In the validation set, the score yielded a C-index of 0.73 (95% CI 0.72-0.75) in men and 0.70 (95% CI 0.68-0.73) in women for all-cause mortality; it was also predictive of CVD (C-index of 0.76 in men and 0.79 in women) and cancer (C-index of 0.70 in men and 0.67 in women) mortality. Moreover, the association between traditional risk factors and all-cause mortality was largely mediated by cystatin C, C-reactive protein, 25-hydroxyvitamin D, and hemoglobin A1c. CONCLUSIONS: We established sex-specific blood biomarker scores for predicting all-cause and cause-specific mortality in the general population, which hold the potential to identify high-risk individuals and improve targeted prevention of premature death.

LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5.

Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.

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.

Association of the interaction between mosaic chromosomal alterations and polygenic risk score with the risk of lung cancer: an array-based case-control association and prospective cohort study.

BACKGROUND: Mosaic chromosomal alterations (mCAs) detected from blood-derived DNA are large structural alterations of clonal haematopoietic origin and are associated with various diseases, such as haematological malignancies, infections, and solid cancers. We aimed to investigate whether mCAs contribute to the risk of lung cancer and modify the effect of polygenic risk score (PRS) on lung cancer risk prediction. METHODS: The blood-derived DNA of patients with lung cancer and cancer-free controls with Chinese ancestry from the Nanjing Lung Cancer Cohort (NJLCC) study were genotyped with a Global Screening Array, and mCAs were detected with the Mosaic Chromosomal Alterations (MoChA) pipeline. mCA call sets of individuals with European ancestry were obtained from the prospective cohort UK Biobank (UKB) study, including documented incident lung cancer. All patients with lung cancer from the NJLCC study (aged 15 years or older at diagnosis) were histopathologically confirmed as new lung cancer cases by at least two pathologists and were free of chemotherapy or radiotherapy before diagnosis. Participants with incident lung cancer (aged 37-73 years at assessment) diagnosed after recruitment to the UKB were identified through linkage to national cancer registries. Logistic regression and Cox proportional hazard models were applied to evaluate associations between mCAs and risk of lung cancer in the NJLCC (logistic regression) and UKB (Cox proportional hazard model) studies. FINDINGS: The NJLCC study included 10 248 individuals (6445 [62·89%] men and 3803 [37·11%] women; median age 60·0 years [IQR 53·0-66·0]) with lung cancer and 9298 individuals (5871 [63·14%] men and 3427 [36·86%] women; median age 60·0 years [52·0-65·0]) without lung cancer recruited from three sub-regions (north, central, and south) across China between April 15, 2003, and Aug 18, 2017. The UKB included 450 821 individuals recruited from 22 centres across the UK between March 13, 2006, and Nov 1, 2010, including 2088 individuals with lung cancer (1075 [51·48%] men and 1013 [48·52%] women; median age 63·0 years [IQR 59·0-66·0]), and 448 733 participants were free of lung cancer (204 713 [45·62%] men and 244 020 [54·38%] women; median age 58·0 years [IQR 50·0-63·0]). Compared with non-carriers of mosaic losses, carriers had a significantly increased risk of lung cancer in the NJLCC (odds ratio [OR] 1·81, 95% CI 1·43-2·28; p=6·69 × 10-7) and UKB (hazard ratio [HR] 1·40, 95% CI 1·00-1·95; p=0·048) studies. This increased risk was even higher in patients with expanded cell fractions of mCAs (ie, cell fractions ≥10% vs cell fractions <10%) in the NJLCC (OR 1·61 [95% CI 1·26-2·08] vs 1·03 [0·83-1·26]; p for heterogeneity test=6·41 × 10-3). A significant multiplicative interaction was observed between PRS and mosaic losses on the risk of lung cancer in both the NJLCC (interaction p value=0·030) and UKB (p=0·043). Compared with non-carriers of mosaic loss abnormalities with low genetic risk, participants with expanded mosaic losses (cell fractions ≥10%) and high genetic risk had around a six-times increased risk of lung cancer in the NJLCC study (OR 6·40 [95% CI 3·22-12·69]), and an almost four-times increased risk of lung cancer (HR 3·75 [95% CI 1·86-7·55]) in the UKB study. The additive interaction also contributed a 3·67 (95% CI 0·49-6·85) relative excess risk of developing lung cancer in the NJLCC study, and a 2·15 (0·12-4·19) relative excess risk in the UKB study. INTERPRETATION: mCAs act as a new endogenous indicator for the risk of lung cancer and might be jointly used with PRS to optimise personalised risk stratification for lung cancer. FUNDING: National Natural Science Foundation of China, Outstanding Youth Foundation of Jiangsu Province, Natural Science Foundation of Jiangsu Province, and Postdoctoral Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Untargeted plasma metabolomics for risk prediction of hepatocellular carcinoma: A prospective study in two Chinese cohorts.

Characterization of metabolic perturbation prior to hepatocellular carcinoma (HCC) may deepen the understanding of causal pathways and identify novel biomarkers for early prevention. We conducted two 1:1 matched nested case-control studies (108 and 55 pairs) to examine the association of plasma metabolome (profiled using LC-MS) with the risk of HCC based on two prospective cohorts in China. Differential metabolites were identified by paired t tests and orthogonal partial least-squares discriminant analysis (OPLS-DA). Weighted gene coexpression network analysis (WGCNA) was performed to classify metabolites into modules for identifying biological pathways involved in hepatocarcinogenesis. We assessed the risk predictivity of metabolites using multivariable logistic regression models. Among 612 named metabolites, 44 differential metabolites were identified between cases and controls, including 12 androgenic/progestin steroid hormones, 8 bile acids, 10 amino acids, 6 phospholipids, and 8 others. These metabolites were associated with HCC in the multivariable logistic regression analyses, with odds ratios ranging from 0.19 (95% confidence interval [CI]: 0.11-0.35) to 5.09 (95% CI: 2.73-9.50). WGCNA including 612 metabolites showed 8 significant modules related to HCC risk, including those representing metabolic pathways of androgen and progestin, primary and secondary bile acids, and amino acids. A combination of 18 metabolites of independent effects showed the potential to predict HCC risk, with an AUC of 0.87 (95% CI: 0.82-0.92) and 0.86 (95% CI: 0.80-0.93) in the training and validation sets, respectively. In conclusion, we identified a panel of plasma metabolites that could be implicated in hepatocellular carcinogenesis and have the potential to predict HCC risk.

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; Pnonadjusted  = .003, Padjusted  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.