Integrated genomic analyses of acral and mucosal melanomas nominate novel driver genes

Acral and mucosal melanomas are less common but aggressive subtypes of melanoma. To characterize the landscapes of genomic alterations in these melanoma subtypes, we compiled sequencing data of 240 human acral and mucosal melanoma samples from 11 previously published studies and applied a uniform pipeline to call tumor cell content, ploidy, somatic and germline mutations, as well as CNVs, LOH, and SVs. We nominated PTPRJ, mutated and homozygously deleted in 3.8% (9/240) and 0.8% (2/240) of samples, respectively, as a probable tumor suppressor gene, and FER and SKP2, amplified in 3.8% and 11.7% of samples, respectively, as probable oncogenes. We further identified a long tail of infrequent pathogenic alterations, involving genes such as CIC and LZTR1. Pathogenic germline mutations were observed on MITF, PTEN, ATM and PRKN. We found BRAF V600E mutations in acral melanoma with fewer structural variations, suggesting that they are distinct and related to cutaneous melanomas. Amplifications of PAK1 and GAB2 were more commonly observed in acral melanoma, whereas SF3B1 R625 codon mutations were unique to mucosal melanoma (12.9%). Amplifications at 11q13-14 were frequently accompanied by fusion to a region on chromosome 6q12, revealing a recurrent novel structural rearrangement whose role remains to be elucidated. In conclusion, our meta-analysis expands the catalogue of driver mutations in acral and mucosal melanomas, sheds new light on their pathogenesis and broadens the catalogue of therapeutic targets for these difficult-to-treat cancers.