Maureen J. O’Sullivan

Professor O’Sullivan’s group identified and characterised in 2012 the then only known genetic mutation recurrently seen in Clear Cell Sarcoma of Kidney (CCSK), and have been working on the biologic implications of that mutation (YWHAE-NUTM2 fusion) since then, with very exciting results. Recently, one further mutation was identified in CCSK – this is within the BCOR gene which has a role in epigenetic regulation of gene transcription. Professor O’Sullivan’s group have now studied a very large cohort of cases of CCSK collected from international sources to total 159 tumours for these two genetic mutations. Their findings show distinct subsets of CCSK with the BCOR and YWHAE alterations. They have adopted several technical approaches specifically to investigate the epigenetic effect of BCOR ITD in cells. Their studies on YWHAE-NUTM2 are already advanced and they will be uniquely positioned to draw comparisons between the molecular mechanisms in their contributions to CCSK oncogenesis.

Malignant rhabdoid tumour (MRT), one of the most aggressive human cancers, afflicts very young children and has extremely poor outcomes. Despite its highly malignant nature, MRT bears mutations in just one gene known as SMARCB1. This gene encodes a protein that is important in the organization of the DNA (the genetic blueprint) within the cell thereby having a major influence on which genes are actively expressed within that cell. We have a number of aims, including working out what cell type rhabdoid tumour arises from, as this is not known and can be important in choosing best treatment. The DNA within a cell is arranged into a structure called chromatin and the precise arrangement is quite dynamic and highly regulated. SMARCB1 is a subunit of a multiprotein complex involved in this regulation of chromatin’s organisation. Therefore, we aimed to work out what exactly happens in terms of DNA organisation when SMARCB1 is inactivated (as occurs in the MRT tumour cell setting) and how this contributes to the cancer developing, but then also to establish what happens when we put SMARCB1 back into the tumour cells that are missing it. Revealing the changes in the chromatin that follow on from loss of, and reintroduction of, SMARCB1 would allow for the identification of vulnerabilities in the MRT cancer cell that could be targeted in new treatments for MRT.