Abstract
APOBEC3 cytidine deaminases are largely known for their innate immune protection from viral infections. Recently, members of the family have been associated with a distinct mutational activity in some cancer types. We report a pan-tissue, pan-cancer analysis of RNA-seq data specific to the APOBEC3 genes in 8,951 tumours, 786 cancer cell lines and 6,119 normal tissues. By deconvolution of levels of different cell types in tumour admixtures, we demonstrate that APOBEC3B (A3B), the primary candidate as a cancer mutagen, shows little association with immune cell types compared to its paralogues. We present a pipeline called RESPECTEx (REconstituting SPecific Cell-Type Expression) and use it to deconvolute cell-type specific expression levels in a given cohort of tumour samples. We functionally annotate APOBEC3 co-expressing genes, and create an interactive visualization tool which ‘barcodes’ the functional enrichment (http://fraternalilab.kcl.ac.uk/apobec-barcodes/). These analyses reveal that A3B expression correlates with cell cycle and DNA repair genes, whereas the other APOBEC3 members display specificity for immune processes and immune cell populations. We offer molecular insights into the functions of individual APOBEC3 proteins in antiviral and proliferative contexts, and demonstrate the diversification this family of enzymes displays at the transcriptomic level, despite their high similarity in protein sequences and structures.
Highlights
Human APOBEC3 proteins are a family of seven cytidine deaminases capable of causing cytidine-to-uridine (C>U) mutations on single-stranded DNA molecules
All cohorts of The Cancer Genome Atlas (TCGA) were matched with cell lines in our CCLE dataset, except Adrenocortical carcinoma (ACC), Pheochromocytoma and Paraganglioma (PCPG) and Testicular Germ Cell Tumours (TGCT)
The ubiquitous overexpression of A3B in cancer samples supports the argument [5,10] for this family member being the APOBEC3 deaminase that most likely causes mutational signatures in cancers. (iii) The levels of all seven APOBEC3 mRNAs are high in tumours, in contrast to the specific expression patterns observed in cancer cell lines (Figure 1)
Summary
Human APOBEC3 (apolipoprotein B mRNA editing catalytic polypeptide-like 3) proteins are a family of seven cytidine deaminases capable of causing cytidine-to-uridine (C>U) mutations on single-stranded DNA molecules. A3B overexpression has been documented in breast cancer cell lines and many other tumours, and shows a weak correlation with the level of APOBEC3-signature mutations [5, 10]. Little has been done to unravel the biological basis of APOBEC3 activation in vivo, the regulation of their expression and functions of the different family members, or the mechanisms under which the enzyme interacts with and mutates human genomic DNA. Multiple APOBEC3 proteins, including APOBEC3A (A3A) [11] and haplotype I of APOBEC3H (A3H) [12], have been implicated as the genomic mutators in cancer, alongside A3B. All of them induce mutations on retroviral genomes, and all (except APOBEC3G, or A3G) deaminate
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