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Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma

SIMPLE SUMMARY: Malignant melanoma is a highly metastatic disease disseminating to several distant sites. This potential is also of great clinical impact for patient survival and therapeutic success. Knowledge about melanoma genomics is mainly based on lymphatic or skin metastases derived data, wher...

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Detalles Bibliográficos
Autores principales: Papp, Orsolya, Doma, Viktória, Gil, Jeovanis, Markó-Varga, György, Kárpáti, Sarolta, Tímár, József, Vízkeleti, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657127/
https://www.ncbi.nlm.nih.gov/pubmed/34885093
http://dx.doi.org/10.3390/cancers13235984
Descripción
Sumario:SIMPLE SUMMARY: Malignant melanoma is a highly metastatic disease disseminating to several distant sites. This potential is also of great clinical impact for patient survival and therapeutic success. Knowledge about melanoma genomics is mainly based on lymphatic or skin metastases derived data, whereas data from distant sites is limited. Therefore, an autopsy-based visceral metastasis biobank was established, and an array-based copy number variation (CNV) analysis was performed, focusing primarily on major organs (brain, lung, and liver) and completed partly by proteomic analysis. A unique picture emerged about organ-specific CNV-type distributions or gene alterations, including the frequent loss of DNA damage error genes in brain metastases, the presence of HGF/MET autocrine loop in brain and lung metastases, the traces of immunogenic mimicry exclusive for lung metastases or the correlation of BRAF copy number and mutant allele frequency, especially in lung metastases. All these above phenomena have a great influence on therapy efficacy or resistance. ABSTRACT: Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays (N = 38 samples) to reveal organ specific alterations. Results were partly completed by proteomic analysis. A significant increase of high-copy number gains was found in an organ-specific manner, whereas copy number losses were predominant in brain metastases, including the loss of numerous DNA damage response genes. Amplification of many immune genes was also observed, several of them are novel in melanoma, suggesting that their ectopic expression is possibly underestimated. This “immunogenic mimicry” was exclusive for lung metastasis. We also provided evidence for the possible autocrine activation of c-MET, especially in brain and lung metastases. Furthermore, frequent loss of 9p21 locus in brain metastases may predict higher metastatic potential to this organ. Finally, a significant correlation was observed between BRAF gene copy number and mutant allele frequency, mainly in lung metastases. All of these events may influence therapy efficacy in an organ specific manner, which knowledge may help in alleviating difficulties caused by resistance.