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.

皮肤黑色素瘤的高背景肿瘤突变负担限制了识别驱动这种癌症的显着突变基因（SMG）的能力。为了解决这个问题，我们对 1,000 多个黑色素瘤外显子组进行了突变显着性研究，并结合了癌症基因组图谱中 470 个病例的多组学分析。我们发现了几种同时发生杂合性缺失和功能缺失突变的 SMG，包括PBRM1 、 PLXNC1和PRKAR1A ，它们编码蛋白激酶 A 全酶亚基。将大量肿瘤转录组解卷积为癌症、免疫和基质成分，揭示了与蛋白激酶 A 通路改变相关的黑色素瘤固有的氧化磷酸化特征。我们还鉴定了 X 染色体上的 SMG，包括 RNA 解旋酶DDX3X ，其功能丧失突变仅在男性中观察到。最后，我们发现肿瘤突变负荷和免疫浸润包含关于黑色素瘤患者生存的补充信息。总之，我们的多组学分析提供了对黑色素瘤病因学的见解，并支持特定突变对这种癌症中观察到的性别偏见的贡献。