Establishment And Validation Of Genetic Analysis And Improved Screening Program For Colorectal Cancer In Young And Old In China

Part 1.Genetic comparison of Chinese young-onset and late-onset sporadic colorectal cancerObjective:To compare genetic differences between colorectal cancer(CRC)in Chinese young-onset and late-onset populations based on whole-exome sequencing(WES)data obtained before.And to explore the potential mechanisms of young-onset CRC by gene enrichment analysis and tumor driver genes screening.Methods:Based on WES data from 10 pairs of young-onset and late-onset sporadic CRC samples,the numbers of non-synonymous somatic mutations and copy number variations(CNVs)were analyzed,and the nonparametric rank sum test was carried out.Differential mutation genes of the two groups were used for enrichment analysis by R and were compared with CGC database to screen tentative tumor driver genes.Results:The number of somatic mutations in young-onset CRC was significantly lower than that in late-onset people(P=0.038).For CNV,the number of deletion mutations in young-onset CRC was lower than that in late-onset CRC(P=0.001),and amplification mutations in young-onset CRC tended to be less yet with no significance(P=0.195).Enrichment analysis showed that compared to late-onset group,mutation genes with higher frequencies in young-onset CRC were mainly enriched in eight biological processes,namely Wnt signaling pathway,O-glycan processing,cholesterol efflux and so on.Diver genes for young-onset CRC included BRAF,CTNNB1,EPHA3,FAT4,MSH2,MUC4,RANBP2,and SPEN.Conclusion:The number of somatic mutations and CNVs of young-onset CRC are generally lower than those in late-onset group,and the unique carcinogenesis pathway of young-onset CRC may be related to some specific biological processes and mutated genes.Part 2.Expression and significance of NR1H4 in colorectal cancer analyzed by the combination of multiple databases and RObjective:To analyze the expression level of NR1H4 in CRC,and to explore its tentative carcinogenesis pathways and the effect on the prognosis of CRC patients.Methods:After screening differentially expressed genes in colorectal adenocarcinoma by GEO database,the protein-protein interaction(PPI)network was constructed with STRING database.Besides,Oncomine database was used to verify the differential expression of NR1H4 in CRC and other tumor types,and TCGA and GEPIA were used to analyze the effect of NR1H4 on survival and prognosis of CRC patients.Results:The expression of NR1H4 in various types of tumors including CRC decreased significantly.The enrichment analysis of differentially expressed genes in colorectal adenocarcinoma showed that NR1H4 was enriched in three biological processes and one KEGG pathway,namely inflammatory response,bile acid and bile salt transport,negative regulation of apoptosis process and bile secretion pathway.PPI analysis showed that several genes including NR1H4 might be hub genes of CRC carcinogenesis.The prognosis analysis showed that the overall survival and disease-free survival of colon cancer patients with low NR1H4 expression seemed to be shorter than those with high expression,but the difference was not significant.Conclusion:NR1H4 is significantly under-expressed in CRC,and it may affect the development of CRC through various mechanisms.Part 3.Improvement of Asia-Pacific Colorectal Screening score and evaluation of its use combined with fecal immunochemical testObjective:The Asia-Pacific Colorectal Screening(APCS)score is used for screening high-risk groups of advanced colorectal neoplasia(ACN)patients.This paper aimed to improve the APCS score and evaluate its use with the fecal immunochemical test(FIT)in stratifying the risk of ACN.Methods:This prospective and multicenter study enrolled 955(completed before)and 1201 Chinese asymptomatic participants to form the derivation and validation set,respectively.Participants received the risk factor questionnaire,colonoscopy and FIT.Multiple logistic regression was applied,and C-statistic,sensitivity and negative predictive values(NPVs)were used to compare the screening efficiency.Results:A modified model was developed incorporating age,body mass index(BMI),family history,diabetes,smoking and drinking as risk factors,stratifying subjects into average risk(AR)or high risk(HR).In the validation set,the HR tier group had a 3.4-fold(95%CI 1.8-6.4)increased risk for ACN.The C-statistic for the modified score was 0.69±0.04,and for the original score 0.67±0.04.The sensitivity of the modified APCS score combined with FIT for screening ACN high-risk cohorts was 76.7%compared with 36.7%of FIT alone and 70.0%of the modified APCS score alone.The NPVs of the modified score combined with FIT for ACN were 98.0%compared with 97.0%of FIT alone and 97.9%of the modified APCS score alone.Conclusion:The modified score and its use with the FIT are efficient in selecting the HR group from a Chinese asymptomatic population.