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Organ specific copy number variations in visceral metastases of human melanoma

Papp, Orsolya ; Doma, Viktória ; Gil, Jeovanis LU ; Markó-Varga, György LU ; Kárpáti, Sarolta ; Tímár, József and Vízkeleti, Laura (2021) In Cancers 13(23).
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... (More)

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.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BRAF and NRAS mutant allele frequency, DDR deficiency, Distant organ metastasis, HGF/MET autocrine activation, Immunogenic mimicry
in
Cancers
volume
13
issue
23
article number
5984
publisher
MDPI AG
external identifiers
  • pmid:34885093
  • scopus:85119981973
ISSN
2072-6694
DOI
10.3390/cancers13235984
language
English
LU publication?
yes
id
baa134a0-3676-4dfb-a74b-c0ce44847b71
date added to LUP
2021-12-15 11:48:38
date last changed
2024-06-15 22:46:16
@article{baa134a0-3676-4dfb-a74b-c0ce44847b71,
  abstract     = {{<p>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.</p>}},
  author       = {{Papp, Orsolya and Doma, Viktória and Gil, Jeovanis and Markó-Varga, György and Kárpáti, Sarolta and Tímár, József and Vízkeleti, Laura}},
  issn         = {{2072-6694}},
  keywords     = {{BRAF and NRAS mutant allele frequency; DDR deficiency; Distant organ metastasis; HGF/MET autocrine activation; Immunogenic mimicry}},
  language     = {{eng}},
  number       = {{23}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Organ specific copy number variations in visceral metastases of human melanoma}},
  url          = {{http://dx.doi.org/10.3390/cancers13235984}},
  doi          = {{10.3390/cancers13235984}},
  volume       = {{13}},
  year         = {{2021}},
}