Primary
malignant melanoma of the esophagus (
PMME) is an exceedingly
rare disease with a poor prognosis. The etiology of
PMME remains largely unknown and genetic characteristics are yet to be clarified, essential for identifying potential therapeutic targets and defining treatment guidelines. Here, we performed whole-exome sequencing on 47
formalin-fixed
paraffin-embedded specimens from 18 patients with
PMME, including 23
tumor samples, 6 metastatic lymph nodes, and 18
tumor-adjacent normal tissues. The genomic features of
PMME were comprehensively characterized, and comparative genomic analysis was further performed between these specimens and 398 skin cutaneous
melanomas (SKCM), 67 non-esophagus mucosal
melanomas (NEMM), and 79 uveal
melanomas (UVM). In the
PMME cohort, recurrently mutated driver genes, such as MUC16,
RANBP2, NRAS, TP53, PTPRT, NF1, MUC4, KMT2C, and BRAF, were identified. All
RANBP2 mutations were putatively deleterious, and most affected samples had multipoint mutations. Furthermore,
RANBP2 showed parallel evolution by multiregional analysis. Whole-genome doubling was an early truncal event that occurred before most driver mutations, except for in TP53. An ultraviolet radiation-related mutational signature, SBS38, was identified as specific to epithelial
melanomas and could predict inferior survival outcomes in both
PMME and SKCM patients. Comparing the mutational and copy number landscapes between
PMME and other subtypes of
melanoma revealed that
PMME has a similar genomic pattern and
biological characteristics to SKCM. In summary, we comprehensively defined the key genomic aberrations and mutational processes driving
PMME and suggested for the first time that
PMME may share similar genomic patterns with SKCM; therefore, patients with rare
melanomas, such as
PMME, may benefit from the current treatment used for common cutaneous
melanoma.