Key role of AGO2 and the 8q24 amplicon in regulation of microRNA biogenesis in cancer
1University of Oxford, Oxford, UK
MicroRNA (miRNA) biogenesis requires a range of enzymes, processing, stabilising and transportation factors to produce a functional miRNA. Disruption of component factors can occur by changes at the genomic level including DNA copy number aberrations. Cancer genomes accumulate such genomic changes to promote cancer progression.
Using a comprehensive list of processing machinery genes we explore the effect of genomic amplification on miRNA biogenesis in multiple cancer types with a focus on three integrated genomic datasets from Breast Cancer patients. We compared expression and amplification profiles for the genes to find the most disrupted candidates with a prognostic impact.
AGO2 was identified as frequently amplified (> 26%) as well as exhibiting prognostic relevance (Cox p-value = 0.01424, HR =1.4). It is the central component of the miRNA silencing complex and is responsible for recruiting the mature miRNA to target and thereby silence the mRNA. It is co-amplified with PABPC1 (p<2.2e-16), another component of the RISC. Both are located in the 8q24 region and co-expressed with multiple relevant driver genes including MYC. Interestingly, AGO2 mRNA has a poor prognostic effect independent of MYC (Cox p-value = 2.21e-05, HR =3.3).
This study has highlighted the disruption of an important player in the miRNA biogenesis pathway. Using independent patient sets we show AGO2s role and validate these findings in vitro.