Multi-omic analysis reveals significantly mutated genes and DDX3X as a sex-specific tumor suppressor in cutaneous melanoma.

The high background tumor mutation burden in cutaneous melanoma limits the ability to identify significantly mutated genes (SMGs) that drive this cancer. To address this, we performed a mutation significance study of over 1,000 melanoma exomes, combined with a multi-omic analysis of 470 cases from The Cancer Genome Atlas. We discovered several SMGs with co-occurring loss-of-heterozygosity and loss-of-function mutations, including PBRM1, PLXNC1 and PRKAR1A, which encodes a protein kinase A holoenzyme subunit. Deconvolution of bulk tumor transcriptomes into cancer, immune and stromal components revealed a melanoma-intrinsic oxidative phosphorylation signature associated with protein kinase A pathway alterations. We also identified SMGs on the X chromosome, including the RNA helicase DDX3X, whose loss-of-function mutations were exclusively observed in males. Finally, we found that tumor mutation burden and immune infiltration contain complementary information on survival of patients with melanoma. In summary, our multi-omic analysis provides insights into melanoma etiology and supports contribution of specific mutations to the sex bias observed in this cancer.