Upregulation of the APOBEC3 Family Is Associated with a Poor Prognosis and Influences Treatment Response to Raf Inhibitors in Low Grade Glioma

Abstract

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) has been identified as a group of enzymes that catalyze cytosine deamination in single-stranded (ss) DNA to form uracil, causing somatic mutations in some cancers. We analyzed the APOBEC3 family in 33 TCGA cancer types and the results indicated that APOBEC3s are upregulated in multiple cancers and strongly correlate with prognosis, particularly in low grade glioma (LGG). Then we constructed a prognostic model based on family expression in LGG where the APOBEC3 family signature is an accurate predictive model (AUC of 0.85). Gene mutation, copy number variation (CNV), and a differential gene expression (DEG) analysis were performed in different risk groups, and the weighted gene co-expression network analysis (WGCNA) was employed to clarify the role of various members in LGG; CIBERSORT algorithm was deployed to evaluate the landscape of LGG immune infiltration. We found that upregulation of the APOBEC3 family expression can strengthen Ras/MAPK signaling pathway, promote tumor progression, and ultimately reduce the treatment benefits of Raf inhibitors. Moreover, the APOBEC3 family was shown to enhance the immune response mediated by myeloid cells and interferon gamma, as well as PD-L1 and PD-L2 expression, implying that they have immunotherapy potential. Therefore, the APOBEC3 signature enables an efficient assessment of LGG patient survival outcomes and expansion of clinical benefits by selecting appropriate individualized treatment strategies.

Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma

“…Therefore, APOBEC3C expression denotes enhanced immune activity in the PDAC TME and predicts immunotherapy responses of PDAC. A previous pancancer analysis also revealed that APOBEC and kataegis are associated with programmed death-ligand 1/2 [ 63 ], and the potential of APOBEC for guiding immunotherapy has been affirmed in other tumours [ 64 , 65 ]. In addition, ongoing clinical trials are investigating the practicality of APOBEC in guiding precise tumour therapy [ 66 ], such as NCT02576444 (olaparib, phase II) and NCT03989089 (pembrolizumab, phase II).…”

Acute expression of human APOBEC3B in mice causes lethality associated with RNA editing

“…Although Apobec1 and C-to-U editing have been linked to several biological processes, their dysregulation has also been associated with multiple diseases, including cancer (Luo et al, 2021; Swanton et al, 2015). Under these circumstances, the mechanisms regulating the correct enzyme activity might be lost and substrate availability might differ.…”

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

“…In addition to generating point mutations in regulatory regions, APOBEC3s may further dysregulate gene expression by promoting increased oncogene copy number (Table 3 ). For example, higher APOBEC3 expression has been associated with increased copy number variation of multiple Ras/MAPK regulatory genes such as ATP2B4 , MAPKAPK2 , and USP15 in glioma [ 51 ]. Amplification of EGFR and CDK4 —both known oncogenes—has also been observed in APOBEC3-high gliomas [ 51 ].…”

“…For example, higher APOBEC3 expression has been associated with increased copy number variation of multiple Ras/MAPK regulatory genes such as ATP2B4 , MAPKAPK2 , and USP15 in glioma [ 51 ]. Amplification of EGFR and CDK4 —both known oncogenes—has also been observed in APOBEC3-high gliomas [ 51 ]. The mechanisms through which APOBEC3s facilitate copy number changes remain unknown.…”

“…Fewer T-reg, Th2, and TAM cells Mouse [ 164 ] 3B Activating More tumor-infiltrating lymphocytes Patient [ 165 ] 3B Activating Immune activation in pan-cancer analysis Patient [ 162 ] 3C-H Activating More CD8+ T-cells with greater receptor diversity and cytolytic activity Patient [ 48 ] Bladder 3B Activating Enrichment of immune-related signatures, including IFN-γ Patient [ 46 ] Mutation burden Activating Higher neoantigen loads, activated CD4+ T cells, CD8+ T cells, and M1 cells. Fewer MDSCs and naïve CD4+ T cells Patient [ 160 ] 3B Activating More cytotoxic T-cells with a higher CD8+/CD3+ ratio Patient [ 35 ] Glioma 3B, 3C, 3D, 3F, 3G, 3H Activating Increased myeloid cell infiltration, IFN-γ signaling, and PD-L1/2 expression Patient [ 51 ] Lung 3B Activating More activated CD4+ T cells, CD8+ T cells, and NK cells. Fewer regulatory T cells Patient [ …”