Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks

Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we utilized a Bayesian approach,integrative risk gene selector(iRIGS),to prioritize risk genes at CRC GWAS loci by integrating multi-omics data.As a result,a total of 105 high-confidence risk genes(HRGs)were identified,which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.Among the 105 HRGs,CEBPB,located at the 20q13.13 locus,acted as a transcription factor playing critical roles in cancer.Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK,PI3K-Akt,and Ras signaling.Next,by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls,we elucidated that rs1810503,a putative functional variant regulating CEBPB,was associated with CRC risk(OR=0.90,95%CI=0.86–0.93,P=1.07×10^(−7)).The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls.Mechanistically,the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via longrange promoter-enhancer interactions,mediated by the transcription factor,REST,and thus decreased CRC risk.In summary,our study provides a genetic resource and a generalizable strategy for CRC etiology investigation,and highlights the biological implications of CEBPB in CRC tumorigenesis,shedding new light on the etiology of CRC.

Clinical characteristics and risk factors of COVID-19 patients with chronic hepatitis B:a multi-center retrospective cohort study

The coronavirus disease 2019(COVID-19)has spread globally.Although mixed liver impairment has been reported in COVID-19 patients,the association of liver injury caused by specific subtype especially chronic hepatitis B(CHB)with COVID-19 has not been elucidated.In this multi-center,retrospective,and observational cohort study,109 CHB and 327 non-CHB patients with COVID-19 were propensity score matched at an approximate ratio of 3:1 on the basis of age,sex,and comorbidities.Demographic characteristics,laboratory examinations,disease severity,and clinical outcomes were compared.Furthermore,univariable and multivariable logistic and Cox regression models were used to explore the risk factors for disease severity and mortality,respectively.A higher proportion of CHB patients(30 of 109(27.52%))developed into severe status than non-CHB patients(17 of 327(5.20%)).In addition to previously reported liver impairment markers,such as alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase,and total bilirubin,we identified several novel risk factors including elevated lactate dehydrogenase(≥245 U/L,hazard ratio(HR)=8.639,95%confidence interval(CI)=2.528–29.523;P<0.001)and coagulation-related biomarker D-dimer(≥0.5μg/mL,HR=4.321,95%CI=1.443–12.939;P=0.009)and decreased albumin(<35 g/L,HR=0.131,95%CI=0.048–0.361;P<0.001)and albumin/globulin ratio(<1.5,HR=0.123,95%CI=0.017–0.918;P=0.041).In conclusion,COVID-19 patients with CHB were more likely to develop into severe illness and die.The risk factors that we identified may be helpful for early clinical surveillance of critical progression.

Systematic analysis on expression quantitative trait loci identifies a novel regulatory variant in ring finger and WD repeat domain 3 associated with prognosis of pancreatic cancer

Background:Pancreatic adenocarcinoma(PAAD)is an extremely lethal malignancy.Identification of the functional genes and genetic variants related to PAAD prognosis is important and challenging.Previously identified prognostic genes from several expression profile analyses were inconsistent.The regulatory genetic variants that affect PAAD prognosis were largely unknown.Methods:Firstly,a meta-analysis was performed with seven published datasets to systematically explore the candidate prognostic genes for PAAD.Next,to identify the regulatory variants for those candidate genes,expression quantitative trait loci analysis was implemented with PAAD data resources from The Cancer Genome Atlas.Then,a two-stage association study in a total of 893 PAAD patients was conducted to interrogate the regulatory variants and find the prognostic locus.Finally,a series of biochemical experiments and phenotype assays were carried out to demonstrate the biological function of variation and genes in PAAD progression process.Results:A total of 128 genes were identified associated with the PAAD prognosis in the meta-analysis.Fourteen regulatory loci in 12 of the 128 genes were discovered,among which,only rs4887783,the functional variant in the promoter of Ring Finger and WD Repeat Domain 3(RFWD3),presented significant association with PAAD prognosis in both stages of the population study.Dualluciferase reporter and electrophoretic mobility shift assays demonstrated that rs4887783-G allele,which predicts the worse prognosis,enhanced the binding of transcript factor REST,thus elevating RFWD3 expression.Further phenotypic assays revealed that excess expression of RFWD3 promoted tumor cell migration without affecting their proliferation rate.RFWD3 was highly expressed in PAAD and might orchestrate the genes in the DNA repair process.Conclusions:RFWD3 and its regulatory variant are novel genetic factors for PAAD prognosis.