The somatic mutations found in melanomas reflect the biological processes that govern tumour development. They also help shape how tumours evolve and escape immune regulation. Studying these changes can therefore help to refine our understanding of melanoma progression with the added potential to offer new perspectives for disease management.

Most prior melanoma sequencing studies have focused on advanced disease. Thus, somatic alterations that influence the behaviour of early-stage tumours have not been fully explored. Consequently, in this thesis I study a collection of 524 primary melanomas on which extensive clinical data have been collected for almost two decades. I describe the mutational landscape of these tumours including driver genes, new recurrent variants, mutually exclusive genetic interactions and copy number alterations. I discuss and associate these features with aspects of tumour pathology, sun exposure, immunogenicity and patient outcomes. To identify genes required for melanoma survival, I intersect my genomic analysis with a dataset of CRISPR-Cas9 dropout screens and discover a melanoma-associated genetic vulnerability mediated by Interferon Regulatory Factor 4 (IRF4). I then begin to experimentally validate and explore the biological pathway by which IRF4 may function in the context of melanoma.

Checkpoint inhibitors have revolutionised melanoma care, yet only a minority of patients respond to these treatments and our comprehension of the mechanisms governing PD-L1 expression on melanoma cells is still limited. In the second part of this thesis, I examine the regulation of the key checkpoint receptor PD-L1, which is often upregulated in melanoma to facilitate tumour escape. To improve our understanding of the processes controlling PD-L1 expression, and how the PD-1/PD-L1 axis can be targeted to overcome immune evasion, I employ a genome-wide CRISPR-Cas9 screening approach. I identify genes which elicit downregulation of PD-L1 when disrupted in melanoma cells, capturing several central processes including basal transcription, N-linked glycosylation and intracellular transport. A second extensive screen in eight cancer cell lines of melanoma, bladder and lung cancer origin validate these findings and link novel candidate genes, including Sphingolipid Transporter 1 (SPNS1), to the control of PD-L1 cell surface expression. Additional work is required to further validate and understand the regulation of PD-L1 through SPNS1, as well as its contribution to immune surveillance.

In summary, I present the first comprehensive evaluation into the somatic alteration landscape of primary melanomas, gaining insight into the molecular architecture of these tumours. Additionally, I introduce novel genes and processes regulating PD-L1 gene transcription, processing and presentation on the cell surface. Collectively, these results improve our understanding of the genetic processes that govern primary melanomas, as well as providing valuable insights into the mechanism of PD-L1 regulation.