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Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by leveraging two-stage case-control study (1738 hepatitis B [HBV]) related HCC cases and 1988 HBV persistent carriers) and biological assays, we identified that rs2647046 was significantly associated with HCC risk (odds ratio = 1.26, 95% CI = 1.11 to 1.43, P = 4.14 × 10−4). Luciferase reporter assays and electrophoretic mobility shift assays showed that rs2647046 A allele significantly increased transcriptional activity via influencing transcript factor binding affinity. Allele-specific chromosome conformation capture assays revealed that enhancer with rs2647046 interacted with the HLA-DQB1-AS1 promoter to allele-specifically influence its expression by CTCF-mediated long-range loop. Cell proliferation assays indicated that HLA-DQB1-AS1 is a potential oncogene in HCC. Our study showed HLA-DQB1-AS1 regulated by a causal SNP in a long-range interaction manner conferred the susceptibility to HCC, suggesting an important mechanism of modulating lncRNA expression for risk-associated SNPs in the etiology of HCC.

The activating transcription factor 1 (ATF1) has been identified as a vital pathogenic factor in the progression of colorectal cancer (CRC), whiles, the precise regulatory mechanisms remain elusive. Here, we comprehensively characterized the ATF1 cistrome by RNA-seq and ChIP-seq assays in CRC cell lines. As the results, we identified 358 genes differentially regulated and 15,029 ATF1 binding sites and demonstrated that ATF1 was widely involved in major signaling pathways in CRC, such as Wnt, TNF, Jak-STAT. Subsequently, by the expression quantitative trait loci (eQTL) analyses, we found that rs7017386 was associated with the expression of CCAT1 and PVT1 in the Wnt pathway. By a two-stage population study with 6,131 CRC cases and 10,022 healthy controls, we identified the variant was associated with CRC risk. Mechanistically, we found rs7017386 allele-specifically enhanced the binding affinity of ATF1 and promoted the expressions of PVT1 and CCAT1, via forming a long-range chromatin loop. Moreover, those two lncRNAs could synergistically facilitate c-Myc expression to activate the Wnt pathway in CRC progression. Our findings not only demonstrated the transcriptomic profiling of ATF1 in CRC, but also provided important clues for the etiology of CRC.

The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear.To investigate the associations between early-life tobacco exposures as well as their interactions with polygenic risk scores (PRSs) and lung cancer incidence and mortality.A total of 432,831 participants from the UK Biobank study were included. We estimated the associations of in utero exposure to tobacco smoke, the age of smoking initiation and their interactions with PRSs with lung cancer incidence and mortality in adulthood using Cox proportional hazard models.Lung cancer incidence [hazard ratio (HR): 1.59, 95% confidence interval (CI), 1.44-1.76] increased among participants with in utero tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer incidence for smoking initiation in adulthood, adolescence, and childhood (vs. never smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79) (Ptrend0.001). Similar findings were observed in lung cancer mortality. Participants with high PRSs and in utero tobacco exposure (vs. low PRSs participants without in utero exposure) had HR of 2.35 for lung cancer incidence (95%CI, 1.97-2.80, Pinteraction=0.089) and 2.43 for mortality (95% CI, 2.05-2.88, Pinteraction=0.032). High PRSs with smoking initiation in childhood (vs. never smokers with low PRSs) had HR of 18.71 for incidence (95% CI, 14.21-24.63, Pinteraction=0.004) and 19.74 for mortality (95%CI, 14.98-26.01, Pinteraction=0.033).In utero and childhood/adolescence exposure to tobacco smoke and its interaction with genetic factors may substantially increase the risks of lung cancer incidence and mortality in adulthood.

Introduction Maintenance hemodialysis (MHD) patients are highly threatened in the novel coronavirus disease 2019 (COVID‐19) pandemic, but evidence of risk factors for mortality in this population is still lacking. Methods We followed outcomes of the overall MHD population of Wuhan, including 7154 MHD patients from 65 hemodialysis centers, from January 1 to May 4, 2020. Among them, 130 were diagnosed with COVID‐19. The demographic and clinical data of them were collected and compared between survivors and nonsurvivors. Results Compared to the corresponding period of last year, the all‐cause mortality rate of the Wuhan MHD population significantly rose in February, and dropped down in March 2020. Of the 130 COVID‐19 cases, 51 (39.2%) were deceased. Advanced age, decreased oxygen saturation, low diastolic blood pressure (DBP) on admission, and complications including acute cardiac injury (HR 5.03 [95% CI 2.21–11.14], p

The screening yield and related cost of a risk-adapted screening approach compared with established screening strategies in population-based colorectal cancer (CRC) screening are not clear.We randomly allocated 19,373 participants into 1 of the 3 screening arms in a 1:2:2 ratio: (1) one-time colonoscopy (n = 3883); (2) annual fecal immunochemical test (FIT) (n = 7793); (3) annual risk-adapted screening (n = 7697), in which, based on the risk-stratification score, high-risk participants were referred for colonoscopy and low-risk ones were referred for FIT. Three consecutive screening rounds were conducted for both the FIT and the risk-adapted screening arms. Follow-up to trace the health outcome for all the participants was conducted over the 3-year study period. The detection rate of advanced colorectal neoplasia (CRC and advanced precancerous lesions) was the main outcome. The trial was registered in the Chinese Clinical Trial Registry (number: ChiCTR1800015506).In the colonoscopy, FIT, and risk-adapted screening arms over 3 screening rounds, the participation rates were 42.4%, 99.3%, and 89.2%, respectively; the detection rates for advanced neoplasm (intention-to-treat analysis) were 2.76%, 2.17%, and 2.35%, respectively, with an odds ratio (OR)The risk-adapted approach is a feasible and cost-favorable strategy for population-based CRC screening and therefore could complement the well-established one-time colonoscopy and annual repeated FIT screening strategies. (Chinese Clinical Trial Registry; ChiCTR1800015506).

BackgroundSquamous 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.MethodsAn 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.ResultsWe 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.ConclusionThese 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.

The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable morbidity and mortality. Tocilizumab, an inhibitor of IL-6, has been widely repurposed as a treatment of severely ill patients without robust evidence supporting its use. In this study, we aimed to systematically describe the effectiveness of treatment and prevention of the cytokine storms in COVID-19 patients with tocilizumab. In this multicentered retrospective and observational cohort study, 65 patients with COVID-19 receiving tocilizumab and 130 not receiving tocilizumab were propensity score matched at a ratio of 2:1 based on age, sex, and comorbidities from January 20, 2020 to March 18, 2020 in Wuhan, China. After adjusting for confounding, the detected risk for in-hospital death was lower in the tocilizumab group versus nontocilizumab group (hazard ratio = 0.47; 95% confidence interval = 0.25–0.90; p = 0.023). Moreover, use of tocilizumab was associated with a lower risk of acute respiratory distress syndrome (odds ratio = 0.23; 95% confidence interval = 0.11–0.45; p < 0.0001). Furthermore, patients had heightened inflammation and more dysregulated immune cells before treatment, which might aggravate disease progression. After tocilizumab administration, abnormally elevated IL-6, C-reactive protein, fibrinogen, and activated partial thromboplastin time decreased. Tocilizumab may be of value in prolonging survival in patients with severe COVID-19, which provided a novel strategy for COVID-19–induced cytokine release syndrome. Our findings could inform bedside decisions until data from randomized, controlled clinical trials become available.

N6-Methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in m6A modification genes, including its “writers”, “erasers” and “readers”, might affect the m6A functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case–control study in Chinese population to interrogate all SNPs in 22 m6A modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3′UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12–1.32, P = 2.39 × 10–6). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an m6A “reader”, hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of m6A modification in tumorigenesis.

Studies on the association between healthy lifestyle and cancer risk are limited among the old Chinese population. The healthy lifestyle score was derived from smoking, drinking, diet, body mass index and physical activity among 23734 retired employees from the Dongfeng-Tongji Cohort. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). The rate advancement periods (RAPs) and the population attributable risk percentage (PAR%) were estimated to indicate the benefits of removing risk lifestyle factors. During a median follow-up of 8.16 years, 2023 cancer cases were identified. Compared with 0–2 points of the healthy lifestyle score, the HRs were 0.87 (95% CI: 0.76, 0.99), 0.83 (95% CI: 0.73, 0.94), and 0.74 (95% CI: 0.64, 0.86) for 3, 4, and 5 points, respectively, with the corresponding RAPs of −4.40 (95% CI: −8.39, −0.41), −5.84 (95% CI: −9.77, −1.90), and −9.14 (95% CI: −14.03, −4.25), respectively. Approximately 15% of incident cancer cases among total population and 22% among men would be prevented by following all 5 healthy lifestyle factors. The current study suggests that healthy lifestyle could reduce cancer risk in the retired Chinese population, especially in males.Key messagesHealthy lifestyle derived by smoking, drinking, diet, body mass index and physical activity presented a strong protective effect on cancer risk among the retired Chinese population, especially in males.We employed the rate advancement periods and the population attributable risk percentage to indicate the benefits of adopting healthy lifestyle and we found that following all 5 healthy lifestyle factors could delay the risk of developing cancer by 9.14 years and prevent 15% of incident cancer cases. Healthy lifestyle derived by smoking, drinking, diet, body mass index and physical activity presented a strong protective effect on cancer risk among the retired Chinese population, especially in males. We employed the rate advancement periods and the population attributable risk percentage to indicate the benefits of adopting healthy lifestyle and we found that following all 5 healthy lifestyle factors could delay the risk of developing cancer by 9.14 years and prevent 15% of incident cancer cases.

Background Reports indicate that those most vulnerable to developing severe coronavirus disease 2019 (COVID-19) are older adults and those with underlying illnesses, such as diabetes mellitus, hypertension, or cardiovascular disease, which are common comorbidities among patients undergoing maintenance hemodialysis. However, there is limited information about the clinical characteristics of hemodialysis patients with COVID-19 or about interventions to control COVID-19 in hemodialysis centers. Methods We collected data retrospectively through an online registration system that includes all patients receiving maintenance hemodialysis at 65 centers in Wuhan, China. We reviewed epidemiologic and clinical data of patients with laboratory-confirmed COVID-19 between January 1, 2020 and March 10, 2020. Results Of 7154 patients undergoing hemodialysis, 154 had laboratory-confirmed COVID-19. The mean age of the 131 patients in our analysis was 63.2 years; 57.3% were men. Many had underlying comorbidities, with cardiovascular disease (including hypertension) being the most common (68.7%). Only 51.9% of patients manifested fever; 21.4% of infected patients were asymptomatic. The most common finding on chest computed tomography (CT) was ground-grass or patchy opacity (82.1%). After initiating comprehensive interventions-including entrance screening of body temperature and symptoms, universal chest CT and blood tests, and other measures-new patients presenting with COVID-19 peaked at 10 per day on January 30, decreasing to 4 per day on February 11. No new cases occurred between February 26 and March 10, 2020. Conclusions We found that patients receiving maintenance hemodialysis were susceptible to COVID-19 and that hemodialysis centers were high-risk settings during the epidemic. Increasing prevention efforts, instituting universal screening, and isolating patients with COVID-19 and directing them to designated hemodialysis centers were effective in preventing the spread of COVID-19 in hemodialysis centers.

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17–1.36; P = 2.57 × 10–9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer–promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology. Significance: This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer–promoter interaction loops.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.DesignWe first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.ResultsWe identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A ‘writer’ complex (METTL13/METTL14/WTAP) and the m6A ‘reader’ YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC.ConclusionsThese findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.

INTRODUCTION In colorectal cancer screening, implementing risk-adapted screening might be more effective than traditional screening strategies. We aimed to compare the effectiveness of a risk-adapted screening strategy with colonoscopy and fecal immunochemical test (FIT) in colorectal cancer screening. METHODS A randomized controlled trial was conducted in 6 centers in China since May 2018. Nineteen thousand five hundred forty-six eligible participants aged 50-74 years were recruited and randomly allocated into 1 of the 3 screening groups in a 1:2:2 ratio: (i) one-time colonoscopy (n = 3,916), (ii) annual FIT (n = 7,854), and (iii) annual risk-adapted screening (n = 7,776). Based on the risk-stratification score, high-risk subjects were referred for colonoscopy and low-risk ones were referred for FIT. All subjects with positive FIT were referred for diagnostic colonoscopy. The detection rate of advanced neoplasm was the primary outcome. The study is registered with the China Clinical Trial Registry (www.chictr.org.cn Identifier: ChiCTR1800015506). RESULTS For baseline screening, the participation rates of the colonoscopy, FIT, and risk-adapted screening groups were 42.5% (1,665/3,916), 94.0% (7,386/7,854), and 85.2% (6,628/7,776), respectively. For the intention-to-screen analysis, the detection rates of advanced neoplasm were 2.40% (94/3,916), 1.13% (89/7,854), and 1.66% (129/7,776), with odds ratios (95% confidence intervals) of 2.16 (1.61-2.90; P < 0.001) for colonoscopy vs FIT, 1.45 (1.10-1.90; P < 0.001) for colonoscopy vs risk-adapted screening, and 1.49 (1.13-1.97; P < 0.001) for risk-adapted screening vs FIT, respectively. The numbers of subjects who required a colonoscopic examination to detect 1 advanced neoplasm were 18 in the colonoscopy group, 10 in the FIT group, and 11 in the risk-adapted screening group. DISCUSSION For baseline screening, the risk-adapted screening approach showed a high participation rate, and its diagnostic yield was superior to that of FIT at a similarly low load of colonoscopy.

Background: Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms. Methods: Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case–control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR–Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes. Results: The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82–0.92, P = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of CD9 and PLEKHG6, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma. Conclusions: Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma. Impact: These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.

Our previous study identified a tag single-nucleotide polymorphism (SNP) rs204900 in TNXB associated with risk of esophageal squamous-cell carcinoma (ESCC) in the Chinese population. However, the functional role of TNXB and causal variants had not been interrogated in that study. In the present study, we explored the effects of TNXB expression in the development of ESCC and searched for functional variants in this gene. We found TNXB was downregulated in ESCC tumors. Using small interfering RNAs and CRISPR-Cas9 methods, we identified that both knockdown and knockout of TNXB significantly promoted ESCC cell growth in vitro, suggesting a tumor suppressor role of this gene in ESCC. Through further fine-mapping analysis, we identified that a noncoding variant in the promoter of TNXB, rs411337, predisposed to ESCC risk (odds ratio = 1.36, 95% confidence interval: 1.22-1.51, P = 9.10 × 10-9 ). These findings revealed the functional mechanism of TNXB in the development of ESCC and may contribute to the prevention and treatment of this disease in the future.

As promising biomarkers and therapy targets, microRNAs (miRNAs) are involved in various physiological and tumorigenic processes. Genetic variants in miRNA‐binding sites can lead to dysfunction of miRNAs and contribute to disease. However, systematic investigation of the miRNA‐related single nucleotide polymorphisms (SNPs) for pancreatic cancer (PC) risk remains elusive. We performed integrative bioinformatics analyses to select 31 SNPs located in miRNA‐target binding sites using the miRNASNP v2.0, a solid database providing miRNA‐related SNPs for genetic research, and investigated their associations with risk of PC in two large case‐control studies totally including 1847 cases and 5713 controls. We observed that the SNP rs3802266 is significantly associated with increased risk of PC (odds ratio (OR) = 1.21, 95% confidence intervals (CI) = 1.11‐1.31, P = 1.29E‐05). Following luciferase reporter gene assays show that rs3802266‐G creates a stronger binding site for miR‐181a‐2‐3p in 3′ untranslated region (3′UTR) of the gene ZHX2. Expression quantitative trait loci (eQTL) analysis suggests that ZHX2 expression is lower in individuals carrying rs3802266‐G with increased PC risk. In conclusion, our findings highlight the involvement of miRNA‐binding SNPs in PC susceptibility and provide new clues for PC carcinogenesis.

Interpreting disease-causing variants, especially in noncoding regions by genome-wide association studies (GWAS), has become one of the most challenging and demanding tasks. We hypothesized that functional lncRNAs variants in GWAS-identified loci might alter expression level of genes associated with persistent HBV infection and hepatocellular carcinoma (HCC). Integrated bioinformatics approaches were used to prioritize potentially functional variants and a two-stage case–control study (2473 HBV positive HCC patients, 2248 persistent HBV carriers and 2294 spontaneously recovered subjects) was performed to assess the roles of these variants. The rs2844512 G > C variant in LINC01149 was identified to facilitate HBV spontaneous recovery (OR = 0.84, 95% CI = 0.77–0.92) but increase the risk of HCC (OR = 1.21, 95% CI = 1.11–1.32) in combined samples. Subsequent biological assays indicated this variant created a binding site for miR-128-3p and upregulated MICA expression by serving as a miRNA sponge, which might recruit NK-cells to lyse infected cells, but release highly soluble MICA by shedding to induce NK-cells exhaustion and tumor immune evasion. These findings highlight a regulatory circuit between LINC01149 and MICA, mediating by miR-128-3p, and the important role of upregulated MICA in conferring susceptibility to persistent HBV infection and HCC.

The N6 -Methyladenosine (m6 A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m6 A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10-8 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m6 A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m6 A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m6 A level, highlighting a clinical potential of variants-associated m6 A modification as a risk marker for CRC prevention.

Background: Estimation of absolute risk of developing colorectal neoplasm is essential for personalized colorectal cancer (CRC) screening. We developed models to determine relative and absolute risks of colorectal neoplasm based on lifestyle and genetic variants and to validate their application in risk-adapted screening.Methods: We prospectively collected data from 203 advanced neoplasms, 464 non-advanced adenomas, and 1,213 healthy controls from a CRC screening trial in China in 2018–2019. The risk prediction model based on four lifestyle factors and a polygenic risk score (PRS) consisted of 19 CRC-associated single-nucleotide polymorphisms. We assessed the relative and 10-year absolute risks of developing colorectal neoplasm and the yield of a risk-adapted screening approach incorporating risk models, fecal immunochemical test, and colonoscopy.Results: Compared to the participants with favorable lifestyle and lower PRS, those with unfavorable lifestyle and higher PRS had 2.87- and 3.79-fold higher risk of colorectal neoplasm in males and females, respectively. For a 50-year-old man or a 50-year-old woman with the highest risk profile, the estimated 10-year absolute risk of developing colorectal neoplasm was 6.59% (95% CI: 6.53–6.65%) and 4.19% (95% CI: 4.11–4.28%), respectively, compared to 2.80% (95% CI: 2.78–2.81%) for men and 2.24% (95% CI: 2.21–2.27%) for women with the lowest risk profile. The positive predictive value for advanced neoplasm was 31.7%, and the number of colonoscopies needed to detect one advanced neoplasm was 3.2.Conclusion: The risk models, absolute risk estimates, and risk-adapted screening presented in our study would contribute to developing effective personalized CRC prevention and screening strategies.

BACKGROUND Bisphenols and triclosan (TCS) are common endocrine disrupters (EDCs) that may induce oxidative stress. However, there is limited information as to whether these EDCs interact with genetic variants to modify the levels of oxidative stress on a genome-wide scale. METHODS We first performed a genome-wide scan among a Chinese population and also measured three urinary EDCs, including bisphenol A (BPA), bisphenol F (BPF) and TCS, and three urinary oxidative stress markers [4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), 8-iso-prostaglandin-F2α (8-isoPGF2α) and 8-hydroxy-deoxyguanosine (8-OHdG)]. Subsequently, we examined interactions between three urinary EDCs and nearly 4.6 million genetic variants for three urinary oxidative stress markers by the general linear model. RESULTS Urinary BPA, BPF and TCS were positively associated with HNE-MA, 8-isoPGF2α and 8-OHdG. Significant rs6855040 (4p15.32/between SNORA75B and QDPR)-BPA, rs1112943 (4q35.1/SNX25)-TCS interactions were associated with the 8-isoPGF2α levels (all P

Background Esophageal squamous cell carcinoma (ESCC) is one of the common gastrointestinal malignancy with an inferior prognosis outcome. DNA replication licensing aberration induced by dysregulation of minichromosome maintenance proteins (MCMs) causes genomic instability and cancer metastasis. SUMOylation modification plays a pivotal role in regulation of genomic integrity, while its dysregulation fueled by preexisting germline variants in cancers remains poorly understood. Methods Firstly, we conducted two‐stage survival analysis consisting of an exome‐wide association study in 904 ESCC samples and another independent 503 ESCC samples. Then, multipronged functional experiments were performed to illuminate the potential biological mechanisms underlying the promising variants, and MCM10 influences the ESCC progression. Finally, we tested the effects of MCM10 inhibitors on ESCC cells. Results A germline variant rs2274110 located at the exon 15 of MCM10 was identified to be significantly associated with the prognosis of ESCC patients. Individuals carrying rs2274110‐AA genotypes confer a poor survival (hazard ratio = 1.61, 95% confidence interval = 1.35–1.93, p = 1.35 × 10−7), compared with subjects carrying rs2274110‐AG/GG genotypes. Furthermore, we interestingly found that the variant can increase SUMOylation levels at K669 site (Lys[K]699Arg[R]) of MCM10 protein mediated by SUMO2/3 enzymes, which resulted in an aberrant overexpression of MCM10. Mechanistically, aberrant overexpression of MCM10 facilitated the proliferation and metastasis abilities of ESCC cells in vitro and in vivo by inducing DNA over‐replication and genomic instability, providing functional evidence to support our population finding that high expression of MCM10 is extensively presented in tumor tissues of ESCC and correlated with inferior survival outcomes of multiple cancer types, including ESCC. Finally, MCM10 inhibitors Suramin and its analogues were revealed to effectively block the metastasis of ESCC cells. Conclusions These findings not only demonstrate a potential biological mechanism between aberrant SUMOylation, genomic instability and cancer metastasis, but also provide a promising biomarker aiding in stratifying ESCC individuals with different prognosis, as well as a potential therapeutic target MCM10., A two‐stage survival study consisting of 1407 subjects finds a significant association between MCM10‐rs2274110 and ESCC survival.The MCM10 variant can increase MCM10 SUMOylation levels and result in MCM10 aberrant overexpression, which facilitates ESCC cells proliferation and migration by inducing genomic instability.The MCM10 inhibitors Suramin and its analogues can block ESCC cells metastasis.

FOXA1 is a pioneer transcription factor which has been established as a carcinogenic factor and can regulate the expression of downstream target genes in breast cancer. We hypothesized that genetic variants modulating FOXA1 expression might play a role in the risk of breast cancer. Physical interaction predicted by PreSTIGE analysis and CHIA-PET data integration with cis-expression quantitative trait loci (cis-eQTL) based SNP-FOXA1 analysis were used to identify potentially regulatory variants modulating the expression of FOXA1. Then, we utilized a case–control study consisting of 855 new diagnosed breast cancer cases and 920 controls in the Chinese population to identify breast cancer associated variants. Biological assays were conducted in breast cancer cell lines to illustrate the effects of associated variants on breast cancer risk. We identified that rs7160774 G > A variant was associated with lower risk of breast cancer (OR = 0.77, 95% confidence interval = 0.62–0.96, P = 0.022). Biological experiments indicated that rs7160774[A] allele down-regulated the expression of FOXA1 compared to the G allele by influencing transcription factor binding affinity, thus playing an important role in the development of breast cancer. Our study suggested that the regulatory variant rs7160774 was associated with risk of breast cancer by long-range modulating FOXA1 expression and provided critical insights into pinpoint causal genetic variants.

GWAS-identified 10q22.3 loci with lead SNP rs704017 are significantly associated with CRC risk in both Asian and European populations. However, the functional mechanism of this region is unclear. In this study, we performed a fine-mapping analysis to identify the causal SNPs. To identify potential functional SNPs in linkage disequilibrium with the lead SNP, we searched for the potential target genes using a Hi-C database and an RNA interfering-based on-chip approach. The results indicated that rs12263636 (r2 = 0.41) showed the highest potential to be functional. It resided in a region with enhancer markers and a topologically associating domain. We found that RPS24 was the only gene that significantly promoted the proliferation rate of CRC cells and might have promoter–enhancer interaction with rs12263636. Dual-luciferase reporter assays confirmed that the risk alleles of two variants (rs3740253 and rs7071351) in RPS24 promoter could increase the expression of luciferase. Case control study consisting of 1134 cases and 2039 health controls confirmed that both the two variants were associated with risk of CRC (rs3740253: P = 0.0079, OR = 1.15, 95% CI 1.04–1.28; rs7071351: P = 0.0085, OR = 1.15, 95% CI 1.04–1.28). And plasmid containing mutant haplotypes containing all the three mutations (rs12263636 or rs3740253 and rs7071351) could most significantly increase luciferase expression, compared with any haplotype of the three mutations. The study explained the functional mechanism for the 10q22.3 loci and provided new insights into the prevention and treatment of CRC.

Pancreatic cancer is one of the deadliest malignancies with few early detection tests or effective therapies. PI3K‐AKT signaling is recognized to modulate cancer progression. We previously identified that a genetic variant in PKN1 increased pancreatic cancer risk through the PKN1/FAK/PI3K/AKT pathway. In order to investigate the associations between genetic variations in that pathway and pancreatic cancer prognosis, we conducted a two‐stage survival analysis in a total of 547 Chinese pancreatic cancer patients. Consequently, a variant, rs13167294 A>C in PIK3R1, was significantly associated with poor survival in both stages and with hazard ratio being 1.32 (95% CI = 1.13‐1.56, P = 0.0007) in the combined analysis. Function annotation and prediction suggested that genetic variants in this locus might affect overall survival of pancreatic cancer patients by regulating PIK3R1 expression.

Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affected-control study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR = 1.77, 95% CI = 1.42–2.21, p = 3.16 × 10(−7); P(multiplicative-interaction) = 1.20 × 10(−22); P(additive-interaction) = 6.50 × 10(−3)). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-β, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.

To determine the potential risk factors and construct the predictive model of diabetic risk among a relatively low risk middle-aged and elderly Chinese population. Information of participants was collected in the Dongfeng-Tongji cohort study, a perspective cohort study of Chinese occupational population. The main outcome was incident type 2 diabetes (T2DM). Based on the conventional risk factors of diabetes, we defined low risk participants without underlying diseases such as coronary heart disease, stroke, cancer, dyslipidemia, hypertension, metabolic syndrome, obesity and family history of diabetes. Totally, 4833 participants from the Dongfeng-Tongji cohort study were enrolled, and of them, 171 had an incident diagnosis of T2DM during 4.6 years of follow-up period. A Cox proportional hazards model was used to estimate effects of risk factors. The restricted cubic spline regression and the Youden index were used to explore the optimal cutoffs of risk factors, and the C index was used to assess the discrimination power of prediction models. There were significant linear relationships between BMI/TG level/fasting glucose level and incident diabetic risk among low risk participants. In the restricted cubic spline regression, when fasting glucose level was above 5.4 mmol/L, TG above 1.06 mmol/L and BMI above 22 kg/m2, the HRs (95% CIs) of diabetes were above 1.0. The detailed HRs (95% CI) were 1.29 (1.01, 1.64), 2.57 (1.00, 6.58), and 1.49 (1.00, 2.22), respectively. The optimal cutoff determined by the Yonden index was 1.1 mmol/L for TG, 24 kg/m2 for BMI and 5.89 mmol/L for fasting plasma glucose, respectively. The C index was 0.75 (95% CI: 0.7–0.81) when age, sex, smoke status, physical activity, BMI (

Observational studies indicated that resting heart rate (RHR) was associated with diabetes mellitus (DM) risk; however, it remains unclear whether the association between RHR and DM is causal. We aimed to examine whether there was causal association of RHR with DM risk. A prospective study including 16,201 middle-aged and older Chinese (7031 males and 9170 females) derived from the Dongfeng-Tongji cohort was performed. Cox proportional hazard regression models were conducted to estimate the associations between RHR and incident DM risk. In 7481 participants, 65 single nucleotide polymorphisms related to RHR were genotyped. A genetic risk score (GRS) of RHR was calculated based on the RHR-associated variants. The causal associations of RHR with DM risk were investigated by Mendelian randomization analysis. During a mean (SD) follow-up of 4.5 (0.5) years, 1110 diabetes were identified. Compared with the referential RHR group (≤ 60 beats per minute [bpm]), individuals with RHR > 80 bpm have a higher incident diabetes risk, with a hazard ratio of 1.40 (95% confidence interval [CI], 1.05–1.88). With per SD increase in the weighted genetic risk score, the resting heart rate increased by 0.71 bpm (95% CI 0.49–0.93). By using the GRS to estimate the unconfounded effect, we found that higher resting heart rate did not have a causal effect on diabetes risk (OR 1.00 [95% CI 0.95–1.05]). The present study supported a positive but not a causal association of RHR with incident diabetes risk. More studies are needed to verify our findings.

Introduction and aim It is indicated that high levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are associated with increased incident type 2 diabetes risk. However, whether serum ALT levels could improve the discrimination of type 2 diabetes remains unclear. Methods The data was derived from the Dongfeng-Tongji cohort study, which was established in 2008 and followed until October 2013. A total of 17,173 participants free of type 2 diabetes at baseline were included and 1159 participants developed diabetes after 4.51 (0.61) years of follow-up. Cox proportional hazard regression model was used to calculate the hazard ratios (HRs) for the association between ALT and AST levels with incident diabetes risk. Receiver-operating characteristic (ROC) curves analysis was used to evaluate the predictive accuracy of models incorporating traditional risk factors with and without ALT. Results Compared with the lowest quartile of ALT and AST levels, the highest quartile had a significantly higher risk of developing type 2 diabetes (HR: 2.17 [95% CI: 1.78–2.65] and 1.29 [1.08–1.54], respectively) after adjustment for potential confounders. The addition of ALT levels into the traditional risk factors did not improve the predictive ability of type 2 diabetes, with AUC increase from 0.772 to 0.774; P = 0.86. Conclusions Although elevated ALT or AST levels increased incident type 2diabetes risk, addition of ALT levels into the prediction model did not improve the discrimination of type 2 diabetes.

Bisphenol A (BPA) may induce oxidative stress as well as the toxicity of colon cancer cells. We hypothesized that BPA exposure and interactions with genetic variants might be associated with colorectal cancer (CRC) risk, and the association might be partly mediated by oxidative stress. We measured urinary BPA and three oxidative stress markers [8-iso-prostaglandinF2α (8-isoPGF2α), 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in 275 new CRC cases and 538 healthy controls. A set of 25 genetic variations in 12 candidate DNA repair genes and 5 metabolic enzyme genes were genotyped by Sequenom MassARRAY approach. In multivariable logistic regression, significant positive associations of CRC risk with BPA, 8-OHdG and HNE-MA were observed. Additionally, 8-OHdG, HNE-MA and 8-isoPGF2α were significantly positively associated with BPA (P

Aim This study aimed to identify the functional genes and genetic variants associated with the prognosis of pancreatic ductal adenocarcinoma (PDAC) and reveal the mechanism underlying their prognostic roles. Methods First, we implement a two-stage exome-wide association study in a total of 1070 patients to identify the genetic variant correlated with PDAC prognosis. Then we performed fine mapping through bioinformatics analysis and dual-luciferase reporter assays to reveal the causal functional variant and prognostic gene. Next, we established the gene knockdown, knockout, and overexpression cell lines with small interfering RNA, CRISPR/Cas9, and lentivirus, respectively, and investigated the gene function on cell proliferation and migration in vivo and in vitro. Finally, we performed the RNA-seq to elucidate downstream genes and mechanisms altering PDAC prognosis. Results We identified the CAV1-CAV2 locus tagged by rs8940 was significantly associated with PDAC prognosis, and rs10249656 in the 3′untranslated region of CAV2 was the real functional variant, which upregulated CAV2 expression through abolishing miR-548s binding. We observed upregulated CAV2 in PDAC and the higher expression correlated with worse prognosis. Transient knockdown of CAV2 inhibited PDAC migration without affecting proliferation rate. Knockout of CAV2 suppressed PDAC progression and metastasis, whereas stable overexpression of CAV2 promoted. Overexpressed CAV2 promoted the PDAC progression and metastasis via perturbing genes in the focal adhesion (CCND1, IGTA1, and ZYX) and extracellular matrix organisation (PLOD2, CAST, and ITGA1) pathways mechanically. Conclusion These findings shed light on an important role of CAV2 on PDAC progression and the prognostic impact of its genetic variation.

Objective: This study was intended to investigate the relationship between COVID-19 disease and ovarian function in reproductive-aged women.Methods: Female COVID-19 patients of reproductive age were recruited between January 28 and March 8, 2020 from Tongji Hospital in Wuhan. Their baseline and clinical characteristics, as well as menstrual conditions, were recorded. Differentials in ovarian reserve markers and sex hormones (including anti-Müllerian hormone [AMH], follicle-stimulating hormone [FSH], the ratio of FSH to luteinizing hormone [LH], estradiol [E2], progesterone [P], testosterone [T], and prolactin [PRL] were compared to those of healthy women who were randomly selected and individually matched for age, region, and menstrual status. Uni- and multi-variable hierarchical linear regression analyses were performed to identify risk factors associated with ovarian function in COVID-19 women.Results: Seventy eight patients agreed to be tested for serum hormone, of whom 17 (21.79%) were diagnosed as the severe group and 39 (50%) were in the basal level group. Menstrual status (P = 0.55), menstrual volumes (P = 0.066), phase of menstrual cycle (P = 0.58), and dysmenorrhea history (P = 0.12) were similar without significant differences between non-severe and severe COVID-19 women. Significant lower serum AMH level/proportion (0.19/0.28 vs. 1.12 ng/ml, P = 0.003/0.027; AMH ≤ 1.1 ng/ml: 75/70.4 vs. 49.7%, P = 0.009/0.004), higher serum T (0.38/0.39 vs. 0.22 ng/ml, P < 0.001/0.001) and PRL (25.43/24.10 vs. 12.12 ng/ml, P < 0.001/0.001) levels were observed in basal level and the all-COVID-19 group compared with healthy age-matched control. When adjusted for age, menstrual status and parity variations in multivariate hierarchical linear regression analysis, COVID-19 disease was significantly associated with serum AMH (β = −0.191; 95% CI: −1.177–0.327; P = 0.001), T (β = 0.411; 95% CI: 11.154–22.709; P < 0.001), and PRL (β = 0.497; 95% CI: 10.787–20.266; P < 0.001), suggesting an independent risk factor for ovarian function, which accounted for 3.2% of the decline in AMH, 14.3% of the increase in T, and 20.7% of the increase in PRL.Conclusion: Ovarian injury, including declined ovarian reserve and reproductive endocrine disorder, can be observed in women with COVID-19. More attention should be paid to their ovarian function under this pandemic, especially regarding reproductive-aged women.Clinical Trial Number: ChiCTR2000030015.

N6-Methyladenosine (m