Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma

Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large‐scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence‐profiled 524 American Joint Committee on Cancer Stage I–III primary tumours. Our analysis of these data reveals recurrent driver mutations, mutually exclusive genetic interactions, where two genes were never or rarely co‐mutated, and an absence of co‐occurring genetic events. Further, we intersected copy number calls from our primary melanoma data with whole‐genome CRISPR screening data to identify the transcription factor interferon regulatory factor 4 (IRF4) as a melanoma‐associated dependency. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.