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Lung-only melanoma: UV mutational signature supports origin from occult cutaneous primaries and argues against the concept of primary pulmonary melanoma.

ABSTRACT: Primary pulmonary melanoma (PPM) is an entity recognized by the thoracic WHO classification. However, given the absence of native melanocytes in the lung and the known phenomenon of regression of cutaneous melanomas, the existence of PPM has remained controversial. Herein we investigate clinicopathologic and genomic features of lung-only melanomas with the goal to clarify their site of origin. We identified 10 melanomas involving exclusively lung with no current or previous cutaneous, uveal, or mucosal primaries. Four patients had solitary lesions with mean size of 5.1 cm (range 3.0-10.1 cm), meeting the criteria of PPM. Four patients had 2-3 lesions and 2 patients had >10 lesions. All cases underwent targeted next-generation sequencing interrogating up to 468 cancer genes, which revealed mean tumor mutation burden of 42.6 per megabase (range 1.8 to 126) and frequent mutations involving BRAF, NRAS, NF1, KIT, and KRAS - a genomic profile typical of UV-associated cutaneous melanoma. Mutational signature was assessable for eight cases harboring >20 mutations. This revealed that all evaluable cases harbored a dominant UV signature. In addition, one nonevaluable case harbored a GG > AA TERT promoter variant that is highly specific for UV-mutagenesis. As control groups, using the same methodology, a dominant UV signature was identified in 97% (470/486) of cutaneous melanomas, whereas no lung adenocarcinoma (n = 291) exhibited this signature. Notably, the clinical and pathologic features of solitary melanomas, especially those with large size and epithelioid morphology, closely mimicked primary lung carcinomas, highlighting a major potential for misdiagnosis. In conclusion, presence of a UV signature provides direct evidence that nearly all lung-only melanomas in this series, including solitary lesions meeting the strict criteria of PPM, represent metastases from occult cutaneous melanomas. This suggests that lung-only melanomas should be considered as likely metastatic even in the absence of a known primary melanoma elsewhere.

SUBMITTER: Yang C

PROVIDER: S-EPMC8386291 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cell-cell interaction in skin homeostasis is tightly controlled by adherens junctions (AJs). Alterations in such regulation lead to melanoma development. However, mutations in AJs and their functional consequences are still largely unknown. Methods: Cadherin mutations in skin cutaneous melanoma were identified using sequencing data from TCGA dataset, followed by cross-validation with data from non-TCGA cohorts. Mutations with significant occurrence were subjected to structural prediction using MODELLER and functional protein simulation using GROMACS software. Neo-antigen prediction was carried out using NetMHCpan tool. Cell-based fluorescence reporter assay was used to validate β-catenin activity in the presence of cadherin mutations. Clinical significance was analyzed using datasets from TCGA and other non-TCGA cohorts. Targeted gene exon sequencing and immunofluorescence staining on melanoma tissues were performed to confirm the in silico findings. Results: Highly frequent mutations in type-II classical cadherins were found in melanoma with one unique recurrent mutation (S524L) in the fifth domain of CDH6, which potentially destabilizes Ca2+-binding and cell-cell contacts. Mutational co-occurrence and physical dynamics analyses placed CDH6 at the center of the top-four mutated cadherins (core CDHs; all type-II), suggesting altered heterophilic interactions in melanoma development. Mutations in the intracellular domains significantly disturbed CDH6/β-catenin complex formation, resulting in β-catenin translocation into cytosol or nucleus and dysregulation of canonical Wnt/β-catenin signaling. Although mutations in core CDH genes correlated with advanced cancer stages and lymph node invasion, the overall and disease-free survival times in those patients were longer in patients with wild-type. Peptide/MHC-I binding affinity predictions confirmed overall increased neo-antigen potentials of mutated cadherins, which associated with T-lymphocyte infiltration and better clinical outcomes after immunotherapy. Conclusion: Changes in cell-cell communications by somatic mutations in AJ cadherins function as one of mechanisms to trigger melanoma development. Certain mutations in AJs may serve as potential neo-antigens which conversely benefit patients for longer survival times.

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Lung-only melanoma: UV mutational signature supports origin from occult cutaneous primaries and argues against the concept of primary pulmonary melanoma.

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