APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.
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.
Princess Margaret Cancer Centre, University Health Network, M5G 2M9 Toronto, Canada; Campbell Family Institute for Breast Cancer Research, M5G 2M9 Toronto, Canada; Department of Medical Biophysics, University of Toronto, M5G 1L7 Toronto, Canada; and Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, M5G 2C4 Toronto, Canada.
David W
DW
Cescon
Princess Margaret Cancer Centre, University Health Network, M5G 2M9 Toronto, Canada; Department of Medical Biophysics, University of Toronto, M5G 1L7 Toronto, Canada; and.
Benjamin
B
Haibe-Kains
Princess Margaret Cancer Centre, University Health Network, M5G 2M9 Toronto, Canada; Campbell Family Institute for Breast Cancer Research, M5G 2M9 Toronto, Canada; Department of Medical Biophysics, University of Toronto, M5G 1L7 Toronto, Canada; and tmak@uhnres.utoronto.ca.
Tak W
TW
Mak
D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D030541:Databases, Genetic; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D017384:Sequence Deletion
D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase
cancer; cellular proliferation; mutagenesis