APOBEC3Bexpression 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.cancer | mutagenesis | cellular proliferation T he recent application of next generation sequencing technologies to characterize the landscape of somatic alterations in solid tumors has yielded major insights into the genes and pathways operant in various cancers. In addition, these studies have enabled the identification of distinct patterns of DNA base alterations that reflect underlying mutational processes (1-6). One of the major discoveries of this effort was the high prevalence of C > T transitions occurring in a preferred sequence motif (TCW, thymine/cytosine/adenine or thymine). This pattern is consistent with the deaminase activity of the AID/APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of enzymes, and thus, its identification invoked an endogenous mutator as a significant contributor to the somatic mutational burden across several cancer types (2-9). Based on the sequence motifs, expression levels, and subcellular localization of APOBEC family members, APOBEC3B (A3B) has been implicated as the likely mutator (6-8).Analyses of cell line and tumor datasets have shown that A3B gene expression is up-regulated in malignant vs. normal tissues and epithelial cell lines and have shown correl...

The PKC/NF-κB Signaling Pathway Induces APOBEC3B Expression in Multiple Human Cancers

“…It is possible that downregulation of APOBEC3B and a subsequent decrease in tumor evolution through lowered mutation rates may also contribute to these encouraging clinical responses. Based on substantive prior work from our lab and others demonstrating a major role for APOBEC3B in cancer mutagenesis and correlating high levels of APOBEC3B with poor prognoses for ER-positive breast cancers (46,47), together with the studies presented here, we propose that existing inhibitors of the PKC-NFκB axis such as AEB071 may be repurposed to treat primary tumors in combination with existing therapies and help prevent detrimental outcomes such as drug resistance and metastases.…”

APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication

“…In some samples, up to 70% of all mutations are associated with the APOBEC mutational signature (Supplemental Table 1), confirming that APOBEC mutagenesis may be an important factor for cancer progression and tissue transformation (de Bruin et al 2014;Henderson et al 2014;McGranahan et al 2015). Recently, it was shown that the expression level of APOBEC3B has prognostic potential, and APOBEC was suggested as a target for oncotherapy (Cescon et al 2015).…”

The 29.5 kb APOBEC3B Deletion Polymorphism Is Not Associated with Clinical Outcome of Breast Cancer

“…Moreover, elevated levels of APOBEC3B mRNA have been shown to associate with cellular proliferation, whereas the APOBEC3B deletion polymorphism associated with activation of immune-related genes [16]. Interestingly, increased lymphocytic infiltration has been associated with a favorable outcome in some, but not all subtypes of breast cancer [34,35].…”