Pan-cancer transcriptomic analysis dissects immune and proliferative functions of APOBEC3 cytidine deaminases

• Published in: Nucleic acids research Vol. 47; no. 3; pp. 1178 - 1194
• Main Authors: Ng, Joseph C F, Quist, Jelmar, Grigoriadis, Anita, Malim, Michael H, Fraternali, Franca
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 20.02.2019
• Subjects: APOBEC Deaminases; Cell Line, Tumor; Cell Proliferation; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Cytosine Deaminase - genetics; Cytosine Deaminase - metabolism; Data Resources and Analyses; Gene Expression Profiling; Humans; Immune System - metabolism; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - metabolism; Mutation; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Software; Transcriptome
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gky1316

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.