Genetic biomarkers in uveal melanoma: an exploration using high-resolution array comparative genomic hy-bridization

Uveal melanomas (UM) are aggressive ocular tumours of adults that are typically characterized by chromosomal aberrations such as loss of 1p, 3, 6q, and gain 6p, and 8q. Of these monosomy 3 (M3) and 8q+ are powerful predictors of prognosis. The relationship of changes affecting chromosome 6 is however more ambivalent, having been linked to both good and poor prognosis, and yet both regions have not been well defined, which suggest the presence of one or more oncogenes in 6p and tumour suppressor gene in 6q. Therefore, different chromosome 6 alterations may have a variable impact on the prognosis of UM, and ultimately contain genes that contribute to the development and metastasis of this disease. It is likely that these changes can act as moderators to the tumour outcome. Although UM disseminates haematogenous with high propensity for the liver, and hepatic involvement reported in over 90% of patients, infrequently some patients will however initially present with metastases in sites other than the liver. The aim of this thesis was to address both central issues. Firstly to better understand how genetic biomarkers identify UM that will metastasize, and whether they can be used to further subtype UM. Secondly to see if potential driver genes could be identified that may lead both to an improved understanding of UM metastasis and how to treat it. The approach taken was to use customised high-resolution aCGH. Which, because it was specifically designed for UM, was hoped to identify recurrent focal SCNA that could have been missed by previous studies using lower resolution and unfocussed approaches, such as chromosomal CGH, classical karyotyping, or even BAC arrays. Altogether 137 primary UM were analysed, and as part of a small pilot study possible drivers were further investigated using IHC