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We aimed to elucidate the roles of <jats:italic>APOBEC3A\/3B<\/jats:italic> functional polymorphisms and their influencing factors on the development of cholangiocarcinoma (CCA) and gallbladder cancer (GBC). Polymorphisms at the promoter regions of <jats:italic>APOBEC3A<\/jats:italic> and <jats:italic>APOBEC3B<\/jats:italic> were genotyped in 3231 participants using quantitative PCR. Dual\u2010luciferase reporter assay was applied to investigate the promoter activity. The difference in gene accessibility between CCA cells and GBC cells was analyzed through single\u2010cell transposase accessible chromatin sequencing. The effect of APOBEC3A on apoptosis was examined by cytometry. It is found that rs2267401\u2010G at the <jats:italic>APOBEC3B<\/jats:italic> promoter decreases CCA risk (age\u2010, gender\u2010adjusted odds ratio [AOR], 0.69; 95% confidence interval [CI], 0.51\u20100.94) but increases GBC risk (AOR, 2.04; 95% CI, 1.35\u20103.10). rs2267401\u2010G confers a decreased <jats:italic>APOBEC3B<\/jats:italic> promoter activity in CCA cells but an increased activity in GBC cells, possibly because the transcriptional repressor TFAP2A is over\u2010expressed in CCA. Tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) increases the level of <jats:italic>APOBEC3B<\/jats:italic> via inhibiting TFAP2A expression rather than directly increasing the accessibility of <jats:italic>APOBEC3B<\/jats:italic> promoter. <jats:italic>APOBEC3A<\/jats:italic> promoter rs12157810\u2010C decreased the risks of CCA and GBC, with an AOR (95% CI) of 0.80 (0.66\u20100.97) and 0.75 (0.59\u20100.95), respectively. rs12157810\u2010C upregulated the promoter activity in both CCA and GBC cells. TNF\u2010\u03b1 upregulated the activity of the <jats:italic>APOBEC3A<\/jats:italic> promoter with rs12157810\u2010C via increasing the accessibility of Ets\u20101 p68. <jats:italic>APOBEC3A<\/jats:italic> overexpression attenuates cancer evolution by causing apoptosis, in contrast to <jats:italic>APOBEC3B<\/jats:italic>. The heterogeneity in the transcriptional regulation of APOBEC3B affects the evolutionary potential of cancer cells in the inflammatory microenvironment.<\/jats:p>","DOI":"10.1002\/ijc.33930","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T17:21:53Z","timestamp":1642008113000},"page":"1825-1837","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Transcriptional repression and apoptosis influence the effect of <scp>APOBEC3A<\/scp>\/<scp>3B<\/scp> functional polymorphisms on biliary tract cancer risk"],"prefix":"10.1002","volume":"150","author":[{"given":"Wenbin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Epidemiology Second Military Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Liver Cancer Surgery Third 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