PO-376 SWI/SNF alterations as markers for prognosis and specific treatments in human cancer

Abstract

Introduction The mutational landscape of cancer has been robustly analysed using next generation sequencing (NGS) allowing the identification of somatic mutations in several SWI/SNF chromatin remodelling complex subunits such as SMARCA4 , SMARCA2 , ARID1A , ARID1B , ARID2 and PBRM1 in different tumour types. SWI/SNF complex play a key role in modulating DNA transcription and repair mechanisms that could offer potential explanations of this role in cancer. We hypothesised that other chromatin remodelling genes, not described until now, could also play an important role in cancer develoment. Material and methods We have performed target sequencing of 736 samples, including 178 lung tumours and 88 matched normal tissue, using custom probes designed against the coding sequence of 250 genes including chromatin regulators such as ATP-dependent remodelling complexes, histone modifiers and as well as recurrently mutated cancer genes. Validation of the potential mutations found in the screening was assessed using high-coverage amplicon sequencing. Finally, proliferation, migration and invasion studies in vitro and in vivo were performed to validate the functional impact of chromatin remodeler alterations in cancer cell lines. Results and discussions This comprehensive genomic analysis identified 4900 somatic mutations among all the samples studied. More than 800 of these mutations are located in the genes of the components of the four main ATP-dependent chromatin remodelling complexes (SWI/SNF, ISWI, CHD and INO80). We have seen that SWI/SNF seems to play a more prominent role in cancer development that the other complexes. Additionally, we have identified new members of the complex that could play an important role in cancer development or in different cancer sub-types to the ones already described. Finally, we have performed functional studies that supports this role and opens new therapeutic opportunities to exploit SWI/SNF defects. Conclusion Our results are in agreement with the notion that chromatin structure plays an important role in tumour progression and that some genes coding for components of ATP-dependent chromatin remodelling complexes are bona fide cancer genes essential for tumour development in specific malignancies. Additionally, we show that these deficiencies can be exploited as markers for prognosis and specific therapy.