Disequilibrium betweenBRCA1andBRCA2circular and messenger RNAs plays a role in breast cancer

A bstract Breast cancer is a frequent disease for which the discovery of markers for early detection or prognostic assessment remains challenging. Circular RNAs (circRNAs) are single-stranded structures in closed loops, produced by backsplicing. CircRNA and messenger RNA (mRNA) are generated cotranscriptionally and backsplicing and linear splicing compete against each other. As mRNAs are key players in tumorigenesis, we hypothesize that a balance disruption between circRNAs and mRNAs could promote breast cancer. Hence, we developed an assay for a simultaneous study of circRNAs and mRNAs, called Splice and Expression Analyses by exon Ligation and High Throughput Sequencing (SEALigTHS). Following SEALigHTS validation for BRCA1 and BRCA2 , our hypothesis was tested using an independent research set of 95 pairs of tumour and adjacent normal breast tissues. On this research set, ratios of BRCA1 and BRCA2 circRNAs/mRNAs were significantly lower in tumour breast tissue compared to normal tissue (p=1.6e-09 and p=4.4e-05 for BRCA1 and BRCA2 , respectively). Overall, we developed an innovative method to study linear and backsplicing, described the repertoire of BRCA1 and BRCA2 circRNAs, including 10 novel ones, and showed for the first time that a disequilibrium between BRCA1 and BRCA2 circRNAs and mRNAs plays a role in breast cancer.