Molecular, cellular and clinical characterisation of mosaic variegated aneuploidy syndrome

• Main Author: Hanks, Sandra
• Published: Institute of Cancer Research (University Of London) 2011
• Subjects: 616.99; Cancer Genetics Section
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.530203

Mosaic variegated aneuploidy (MVA) syndrome is an autosomal recessive disorder characterised by mosaic aneuploidies, a variety of phenotypic abnormalities and predisposition to cancer. This study aimed to identify the genetic defect underlying MVA and to characterise the associated cellular and clinical phenotypes. Following a candidate gene screening approach, I identified biallelic BUB1B mutations as a cause of MVA. BUB1B encodes BUBR1 which has multiple, crucial roles in the mitotic spindle checkpoint. I subsequently demonstrated that BUBR1 expression was reduced in BUB1B cases. Furthermore, transfer of human chromosome 15, containing the BUB1B locus, complemented the cellular phenotype in BUB1B mutation-positive cells. As hereditary cancer genes are frequently implicated in sporadic cancers, I undertook mutational analyses of sporadic childhood tumours which confirmed that somatic BUB1B mutations are unlikely to be common in cancers of the types typically associated with MVA. To enable stratification of cases into phenotypically characterised subgroups, I evaluated the molecular, cellular and clinical features associated with MVA. Cases can be classified according to the presence (40%) or absence (60%) of BUB1B mutations. Whilst a strong phenotypic overlap of BUB1B and non-BUB1B cases renders the delineation of clinical subgroups difficult, BUB1B cases do appear to be at higher risk of developing cancer. Karyotypic analyses revealed that there was no apparent correlation between mutation status and the extent of aneuploidies. However, assessment of mitotic checkpoint function demonstrated that the checkpoint defect was profound in BUB1B cases; in contrast, most non-BUB1B cases analysed had intermediate or normal checkpoint function. Our results clearly highlight the heterogeneous nature of MVA syndrome. Furthermore, our data were the first to relate germline mutations in a mitotic checkpoint gene with a human disorder and strongly support a causal role for aneuploidy in cancer development. The aim of future work would be to identify the causative gene(s) in non-BUB1B cases.