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Comprehensive genomic analysis of primary malignant melanoma of the esophagus reveals similar genetic patterns compared with epithelium-associated melanomas


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.

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Fig. 1: The mutation landscape of PMME.
Fig. 2: Copy number alterations in PMMEs.
Fig. 3: Mutational spectrum in PMME and other types of melanomas.
Fig. 4: Comparative mutational landscape of primary melanomas from PMME, SKCM, and MM patients.
Fig. 5: Somatically altered genes in the PMME, SKCM, and MM cohorts were selected and compared in the determined melanoma pathways.
Fig. 6: SBS38, SBS6, and genome instability are associated with poor prognosis in melanoma.

Data availability

The sequence reported in this paper has been deposited in the CNGBdb (China National GeneBank database, under accession number CNP0001947. The remaining data are available within the supplementary files or from the authors upon request.


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We thank all the participants in this study. We would also like to thank Isabella Chao, Diana Hu, Professor Hong Cai and Professor Wenqing Li for their language suggestions.


This study was supported by the National Key R&D Program of China (No. 2018YFC0910700), National Natural Science Foundation of China (81902508, 81972842), Beijing Natural Science Foundation (No. 7192036), Special Fund of Beijing Municipal Administration of Hospitals Clinical Medicine Development (No. XMLX201841) and Beijing Municipal Administration of Hospital’s Ascent Plan (No. DFL20191101).

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Conceptualization: J.J.L., B.L., and N.W.; Methodology: J.J.L., Q.Y., X.X., S.Y., C.X.W., S.L.L., and Y.Q.W.; Data analysis: J.J.L., B.L., X.X., C.X.W., and Z.C.Y.; Investigation: J.J.L., B.L., Z.X.T., and S.M.P.; Resources: W.Y.G., L.H., and Y.Y.M.; Writing and visualization: J.J.L., B.L., Q.Y., and X.X.; Supervision: N.W.; Funding acquisition: J.J.L. and N.W. The authors have read and approved the final manuscript.

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Correspondence to Nan Wu.

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This study was approved by the Ethics Committee of Peking University Cancer Hospital & Institute (Institutional Review Board No. 2019KT59).

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Li, J., Liu, B., Ye, Q. et al. Comprehensive genomic analysis of primary malignant melanoma of the esophagus reveals similar genetic patterns compared with epithelium-associated melanomas. Mod Pathol (2022).

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