Key role of AGO2 and the 8q24 amplicon in regulation of microRNA biogenesis in cancer

Laura Winchester1,Simon Wigfield1,Syed Haider1,Alan McIntyre1,Adrian Harris1,Francesca Buffa1

1University of Oxford, Oxford, UK

Presenting date: Wednesday 4 November


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 AGO2’s role and validate these findings in vitro.