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

Background

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.

Method

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.

Results

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).

Conclusion

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.