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Jurmeister P, Wrede N, Hoffmann I, et al. Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations. J Pathol. 2021;256(1):61-70doi: 10.1002/path.5808.
Jurmeister, P., Wrede, N., Hoffmann, I., Vollbrecht, C., Heim, D., Hummel, M., Wolkenstein, P., Koch, I., Heynol, V., Schmitt, W. D., Thieme, A., Teichmann, D., Sers, C., von Deimling, A., Thierauf, J. C., von Laffert, M., Klauschen, F., & Capper, D. (2022). Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations. The Journal of pathology, 256(1), 61-70. https://doi.org/10.1002/path.5808
Jurmeister, Philipp, et al. "Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations." The Journal of pathology vol. 256,1 (2022): 61-70. doi: https://doi.org/10.1002/path.5808
Jurmeister P, Wrede N, Hoffmann I, Vollbrecht C, Heim D, Hummel M, Wolkenstein P, Koch I, Heynol V, Schmitt WD, Thieme A, Teichmann D, Sers C, von Deimling A, Thierauf JC, von Laffert M, Klauschen F, Capper D. Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations. J Pathol. 2022 Jan;256(1):61-70. doi: 10.1002/path.5808. Epub 2021 Oct 25. PMID: 34564861.
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J Pathol. 2022 Jan;256(1):61-70. doi: 10.1002/path.5808. Epub 2021 Oct 25.

Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations.

The Journal of pathology

Philipp Jurmeister, Niklas Wrede, Inga Hoffmann, Claudia Vollbrecht, Daniel Heim, Michael Hummel, Peggy Wolkenstein, Ines Koch, Verena Heynol, Wolfgang Daniel Schmitt, Anne Thieme, Daniel Teichmann, Christine Sers, Andreas von Deimling, Julia Cara Thierauf, Maximilian von Laffert, Frederick Klauschen, David Capper

Affiliations

  1. Institute of Pathology, Ludwig Maximilians University Hospital Munich, Munich, Germany.
  2. Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  3. German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  4. Berlin Institute of Health (BIH), Berlin, Germany.
  5. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany.
  6. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
  7. Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

PMID: 34564861 DOI: 10.1002/path.5808

Abstract

Cutaneous, ocular, and mucosal melanomas are histologically indistinguishable tumors that are driven by a different spectrum of genetic alterations. With current methods, identification of the site of origin of a melanoma metastasis is challenging. DNA methylation profiling has shown promise for the identification of the site of tumor origin in various settings. Here we explore the DNA methylation landscape of melanomas from different sites and analyze if different melanoma origins can be distinguished by their epigenetic profile. We performed DNA methylation analysis, next generation DNA panel sequencing, and copy number analysis of 82 non-cutaneous and 25 cutaneous melanoma samples. We further analyzed eight normal melanocyte cell culture preparations. DNA methylation analysis separated uveal melanomas from melanomas of other primary sites. Mucosal, conjunctival, and cutaneous melanomas shared a common global DNA methylation profile. Still, we observed location-dependent DNA methylation differences in cancer-related genes, such as low frequencies of RARB (7/63) and CDKN2A promoter methylation (6/63) in mucosal melanomas, or a high frequency of APC promoter methylation in conjunctival melanomas (6/9). Furthermore, all investigated melanomas of the paranasal sinus showed loss of PTEN expression (9/9), mainly caused by promoter methylation. This was less frequently seen in melanomas of other sites (24/98). Copy number analysis revealed recurrent amplifications in mucosal melanomas, including chromosomes 4q, 5p, 11q and 12q. Most melanomas of the oral cavity showed gains of chromosome 5p with TERT amplification (8/10), while 11q amplifications were enriched in melanomas of the nasal cavity (7/16). In summary, mucosal, conjunctival, and cutaneous melanomas show a surprisingly similar global DNA methylation profile and identification of the site of origin by DNA methylation testing is likely not feasible. Still, our study demonstrates tumor location-dependent differences of promoter methylation frequencies in specific cancer-related genes together with tumor site-specific enrichment for specific chromosomal changes and genetic mutations. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: DNA methylation; DNA sequencing; conjunctival melanoma; copy number profiling; cutaneous melanoma; mucosal melanoma; uveal melanoma

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