Grant: Operating Grant

In North America, ovarian cancer is the leading cause of death due to gynaecological malignancies. Ovarian cancers can be divided into subtypes based on their tumour cell types. Clear cell carcinomas of the ovary are one of the ovarian cancer subtypes and represent approximately 12% of all malignant ovarian tumours. For women with this disease, the success of traditional chemotherapy has been limited, suggesting the need for more effective and subtype specific treatments. We have recently shown that over one-third of ovarian clear cell tumours contain mutations in a gene called ARID1A. This gene encodes the BAF250a protein which is a member of a large complex of proteins termed the SWI/SNF complex. This complex is involved in remodelling DNA, ultimately influencing which genes are turned 'on' or 'off'. It may be that mutations in ARID1A and related genes disrupt this regulation, which could result in uncontrolled growth and cancer. Our research team will harness the power of new genomic technologies to investigate the involvement of the SWI/SNF complex of proteins in clear cell cancers of the ovary. We will firmly establish how common mutations in ARID1A and other SWI/SNF genes are in both clear cell tumours of the ovary, other ovarian carcinomas and their precursor lesions. In addition, through carefully designed experiments, we will determine how SWI/SNF proteins influence cell growth and whether this is altered when specific components of the complex are mutated. Finally, it may be that disruption of ARID1A confers a specific sensitivity to cancer cells that could be used to selectively kill these cells as a potential therapy for clear cell cancers of the ovary; this will be investigated through a screening experiment.