%0 Generic
%A Hafermann, Juliane O.
%D 2019
%F heidok:24021
%K APOBEC3A, cytidine deaminase, mutagenesis, head and neck squamous cell carcinoma, mutational signature
%R 10.11588/heidok.00024021
%T The effect of APOBEC3A-mediated mutagenesis on tumour growth of immortalised, transformed cells and on survival of head and neck squamous cell carcinoma patients
%U https://archiv.ub.uni-heidelberg.de/volltextserver/24021/
%X Inflammation and mutagenesis contribute to cancer progression. The cytidine deaminase APOBEC3A might link these two processes. On the one hand, the expression of APOBEC3A is regulated by infections and pro-inflammatory stimuli. On the other hand, APOBEC3A causes mutational signatures that have been found in the genomes of various cancer types. However, the major contribution of APOBEC3A during the process from tumour initiation to a fully formed disease is still under debate. APOBEC3A-mediated mutagenesis could (a) affect early stages of tumour development by mutating cancer driver and/or tumour suppressor genes, (b) have an influence by increasing the total mutational load, or (c) shape the tumour by increasing genetic heterogeneity, in particular during late stages of cancer progression. In addition, it is unclear whether parameters capturing the process of APOBEC3A-mediated mutagenesis during cancer progression have a prognostic value. Here, we address (I) whether APOBEC3A-mediated mutations alter tumour growth of already immortalised, transformed cells and (II) whether a combination of parameters describing past and ongoing APOBEC3-mediated mutagenesis have a prognostic value in a cohort of head and neck squamous cell carcinoma (HNSCC) patients. In this study, we established HEK293 cell populations carrying the APOBEC3-mediated mutational signatures. As ongoing APOBEC3A-driven mutagenesis causes a genetically heterogeneous cell population, single cell clones were isolated and analysed. APOBEC3A activity was lost in these clones by various mechanisms after creating the APOBEC3 mutational signature. The clones were characterised by quantifying proliferation, migration, cisplatin resistance and in vivo tumour growth in a xenograft mouse model. No phenotypic difference was observed between APOBEC3A-mutagenised cells and controls regarding any of the studied phenotypes either in vitro or in vivo. This suggests that APOBEC3A-mediated mutagenesis has no effect on the tumour growth of immortalised and transformed HEK293 cells. These results hint that additional APOBEC3A-mediated mutagenesis in cells with a large number of pre-existing tumourigenic alterations cannot further affect cellular growth. Analysing material from tumour patients with HNSCC revealed that tumours can show APOBEC3A expression and/or APOBEC3B expression and/or the APOBEC3 mutational signature. None of these parameters by themselves succeeded in stratifying an HNSCC cohort. In contrast, a principal component analysis combining transcriptional and genomic data lead to a statistically significant stratification regarding progression-free survival. The approach developed here might be a valuable additional tool in personalised medicine.