Pan-Cancer APOBEC Mutagenesis, Immune Microenvironment, and Clinical Outcome: A Comprehensive Multi-Omics Analysis of All Ten Family Members Across 9653 TCGA Tumors

Abstract

The apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) family comprises ten cytidine deaminases implicated in cancer mutagenesis, yet their broader biological significance remains incompletely understood. We performed an integrated pan-cancer analysis of all ten APOBEC family members across 9653 tumors from 33 cancer types in The Cancer Genome Atlas (TCGA), combining mutational signatures, sequence-context enrichment, transcriptomics, immune microenvironment profiling, stemness, clinical outcomes, and somatic mutation analyses. APOBEC enrichment was detected in 17.6% of tumors and exhibited marked cancer-type specificity, with the highest prevalence in bladder, cervical, and head and neck carcinomas. Associations between binary APOBEC enrichment and advanced stage or poorer survival were largely attenuated after adjustment for cancer type. In contrast, exploratory analysis of continuous APOBEC burden revealed a nonlinear association with mortality, although this relationship showed substantial cancer-specific heterogeneity and requires independent validation. Coding mutations in APOBEC genes were rare, showed no evidence of positive selection, and were not consistently associated with altered expression, indicating that dysregulated expression rather than genetic alteration is the predominant mode of APOBEC involvement in cancer. Most APOBEC3 genes were upregulated in tumors, particularly APOBEC3B, whereas APOBEC2 was broadly downregulated. APOBEC3A, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H were consistently associated with immune infiltration, immune-checkpoint expression, and inflammatory immune-cell populations across multiple analytical platforms. After adjustment for tumor purity and ploidy, most APOBEC family members showed negative associations with stemness, whereas APOBEC3B displayed predominantly positive associations. Collectively, these findings reveal substantial heterogeneity within the APOBEC family and support evaluating individual APOBEC members, particularly APOBEC3A and APOBEC3B, as distinct cancer biomarkers.