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Abstract
Abstract The mutational signatures related to apolipoprotein B mRNA-editing enzyme catalytic polypeptides (APOBECs) are found in many cancers. We aimed to assess the impact of APOBEC3B deletion variant on the risk and prognosis of various cancers in the Golestan Cohort Study, Iran, comprising 1, 393 cancer cases and 1, 806 controls (median age: 69.2 years). The population predominantly consisted of the Turkmen ethnicity (77.5%), with 49.6% of individuals deceased during the study period. The TaqMan genotyping assay was used as a proxy to identify the rs12628403-A/C (linked to intact/deleted APOBEC3B) alleles. The APOBEC3B deletion was identified in 29.8% of individuals. Cancer cases exhibited a higher frequency of APOBEC3B deletion compared to controls, particularly among Turkmen individuals (32.9% vs. 28.5%, OR = 1.23, P = 0.019). Increased frequencies were observed for gastric cancer (OR = 1.61, P = 0.001) and collective gastrointestinal (esophageal, gastric, small intestinal, and colorectal) cancers (OR = 1.31, P = 0.012) among APOBEC3B-deleted individuals. In head and neck cancer, APOBEC3B deletion was more prevalent among cases of all origins (OR = 1.83, P = 0.036). Survival analyses revealed contrasting effects of the APOBEC3B deletion. APOBEC3B deletion was significantly associated with longer survival in pancreatic (4.0 vs. 2.7 months; P = 0.025) and biliary (29.3 vs. 3.1 months; P = 0.047) cancers, as well as the collective hepato-pancreato-biliary (hepatocellular, pancreatic, gallbladder, and biliary) cancers (4.2 vs. 2.5 months; P = 0.002). By contrast, it was predictive of shorter survival in bladder (2.1 vs. 32.8 months; P = 1.1e-4) and cervical (5.7 vs. 53.7 months; P = 0.017) cancers, and the collective genitourinary (bladder, cervical, uterus, and prostate) cancers (5.7 vs. 32.8 months; P = 1.9e-5). Multivariate Cox regression analyses confirmed a favorable prognostic impact of the APOBEC3B deletion in the collective hepato-pancreato-biliary cancers (HR = 0.634; P = 0.039), while an adverse prognostic impact in the genitourinary cancers (HR = 2.45; P = 1.9e-4) and meningioma (HR = 6.750; P = 0.025). These findings suggest the APOBEC3B deletion as a susceptibility and prognostic biomarker in specific cancers, with differential effects based on tumor type. Further studies are warranted to elucidate underlying mechanisms and potential therapeutic implications. Citation Format: Ahmadreza Niavarani, Peyvand Parhizkar Roudsari, Roya Noorbakhsh, Melineh Markarian, Reza Malekzadeh. Differential prognostic impacts of the germline APOBEC3B deletion polymorphism in hepato-pancreato-biliary and genitourinary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7170.
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