Genomic analysis of primary and metastatic malignant melanoma

Abstract

“Cutaneous melanoma is a most unpredictable lesion” wrote Alexander Breslow in 1970. He was one of the first to predict outcome in melanoma patients, based on the thickness of the primary tumor, and today this parameter bears his name and remains the main prognostic factor in melanoma. The aim of this thesis has been to contribute to the understanding of melanoma biology in order to make this cancer more “predictable”. This thesis consists of two parts. The first part addresses the question of progression of melanoma. By analysis of multiple metastatic tumors from the same patient we showed that, although multiple lesions contained a core of molecular aberrations, in most patients each metastasis carried additional individual events. This may illustrate the biological basis for the inherent therapy resistance of melanoma. The majority of the shared single base substitutions carried a signature of UV-induced DNA damage, providing evidence for causal involvement of UV radiation in melanomagenesis. However, the biology of individual metastases within a patient was often very different, as they belonged to different molecular subtypes with distinct gene expression patterns. In one patient, we observed a large number of non-UV mutations in a late stage metastasis, a phenomenon that was not observed in the lesions that had been diagnosed earlier. The second part of this thesis addresses the question of the biological diversity of melanoma. The “unpredictability” of melanoma is reflected by the occasional clinical observation of one or more metastases in patients with thin primary lesions, and cases of thick lesions that remain confined to the primary site. Therefore, additional factors influence prognosis, and these are included in the current staging system. We described gene-expression based grade as an independent prognostic factor in primary melanoma, and even in melanomas with Breslow thickness over 2 mm. High-grade tumors expressed increased levels of cell cycle and DNA damage response and repair genes, while low-grade was associated with elevated expression of immune-response genes. In conclusion, the findings presented in this thesis emphasize the heterogeneity of melanoma with clinical implications