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Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.

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Fig. 1: Morphologic findings in MCC with SCCIS.
Fig. 2: Genomic relatedness in MCC-SCCIS pairs.
Fig. 3: Transcriptome analyses of MCC-SCCIS pairs.
Fig. 4: Shift to neuroendocrine phenotype is associated with changes in Rb protein expression and global H3K27Me3.

Data availability

All nucleotide variants and differentially expressed genes meeting statistical thresholds are listed in supplemental materials. Additional data related to this manuscript can be provided upon request.

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Acknowledgements

We thank the Rogel Cancer Center Tissue and Molecular Pathology Shared Resource (supported by NIH P30 CA04659229) for assistance with tissue processing. We thank Aniket Dagar for bioinformatics assistance. We thank Sharon Kerr, Threase Nickerson, and Karen Myers for administrative support.

Funding

This work was supported by NIH grants CA189352 (A.A.D. and M.E.V.), CA241947 (A.A.D., M.E.V., and P.W.H.), CA046592 (University of Michigan Rogel Cancer Center Support Grant to A.A.D. and P.W.H.), AR075043 (University of Michigan Skin Biology and Diseases Resource-based Center to A.A.D. and P.W.H.), and the AP Project Funding Committee, Department of Pathology, University of Michigan.

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Contributions

Conceptualization: P.W.H., A.M., A.A.D.; Data Curation: K.H., A.M.U.; Formal Analysis: P.W.H., K.H., A.M.U.; Funding Acquisition: P.W.H., M.E.V., M.P.C., A.U.M., A.A.D.; Investigation: M.E.V., K.H., S.M.H., R.M.P., M.P.C., A.M.U., P.W.H.; Methodology: M.E.V., K.H., S.M.H., M.P.C., A.M.U., A.A.D.; Project Administration: C.L., A.M.U., A.A.D.; Resources: M.P.C., R.M.P., A.M.U., A.A.D.; Software: K.H., A.M.U.; Supervision: C.L., M.P.C., A.M.U., A.A.D.; Validation: P.W.H., M.E.V., K.H., S.M.H.; Visualization: P.W.H., M.E.V.; Writing - Original Draft Preparation: P.W.H., M.E.V., A.M.U., A.A.D.; Writing - Review and Editing: P.W.H., M.E.V., K.H., S.M.H., M.P.C., C.L., M.G., R.M.P., A.M.U., A.A.D.

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Correspondence to Paul W. Harms or Andrzej A. Dlugosz.

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This study was conducted under a protocol approved by the Institutional Review Board at the University of Michigan (HUM00045834).

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Harms, P.W., Verhaegen, M.E., Hu, K. et al. Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors. Mod Pathol 35, 506–514 (2022). https://doi.org/10.1038/s41379-021-00928-1

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