APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Abstract

Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B(del)), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B(del) individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B(del) breast cancers, which seems to be related to hypermutation arising in A3B(del) carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B(del) require additional study, these findings nominate the A3B(del) polymorphism as a potential predictor for cancer immunotherapy.

Keywords: cancer; cellular proliferation; mutagenesis.

Fig. 1.

A3B gene expression is associated with clinicopathologic features, including lymph node involvement (P = 3.2 × 10⁻⁴), histologic grade (P = 1.4 × 10⁻⁴⁵), lack of ER expression (P = 4.8 × 10⁻⁴³), and HER2 overexpression/amplification (P = 7.6 × 10⁻⁵), in METABRIC breast cancers. P values are for the global dataset.

Fig. 2.

High A3B gene expression is associated with recurrence after treatment for luminal breast cancer in METABRIC. Kaplan–Meier plots are dichotomized by median A3B expression for all breast cancers (global) or within each intrinsic subtype. P < 0.001 for global, luminals, luminal A, and luminal B. DFS, disease-free survival.

Fig. 3.

A3B gene expression correlates with the Genomic Grade Index (GGI) score in all breast cancers (global: ⍴ = 0.51, P < 1 × 10⁻¹⁶) and within individual intrinsic subtypes (basal: ⍴ = 0.23, P = 3.1 × 10⁻³; Her2: ⍴ = 0.33, P = 1.1 × 10⁻⁴; luminals: ⍴ = 0.55, P < 1 × 10⁻¹⁶; luminal A: ⍴ = 0.39, P = 1.4 × 10⁻¹⁴; luminal B: ⍴ = 0.53, P < 1 × 10⁻¹⁶) in TCGA.

Fig. 4.

A3B gene expression correlates with expression of the proliferation-associated gene AURKA across all breast cancers (global: ⍴ = 0.46, P < 1 × 10⁻¹⁶) and within individual intrinsic subtypes (basal: ⍴ = 0.22, P = 3.8 × 10⁻³; Her2: ⍴ = 0.28, P = 9.8 × 10⁻⁴; luminals: ⍴ = 0.50, P < 1 × 10⁻¹⁶; luminal A: ⍴ = 0.31, P = 1.1 × 10⁻⁹; luminal B: ⍴ = 0.45, P = 8.9 × 10⁻¹⁶) in TCGA.

Fig. 5.

A3B gene expression in TCGA breast cancers is increased in tumors with TP53 mutation (vs. WT) but decreased in tumors with any PIK3CA mutation or the E542K or E545K A3B motif mutations (vs. WT). Similar associations are present across all tumors and within individual subtypes. Note that groups with less than three samples were omitted. MUT, mutation.

Fig. 6.

A3B expression is (A) reduced in TCGA breast cancers from patients with germ-line A3B^del polymorphism (B) without a reciprocal increase in A3A. The A3B^del genotype is not associated with (C) expression of AURKA or (D) the Genomic Grade Index (GGI). Similar patterns are present across all tumors and within intrinsic subtypes.

Fig. 7.

Germ-line A3B^del genotype is not associated with recurrence after treatment for early breast cancer in METABRIC. Kaplan–Meier plots show disease-free survival (DFS) by A3B^del genotype for all breast cancers (global) and by intrinsic subtypes. P > 0.6 for all.