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NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics

Cirenajwis, Helena LU ; Lauss, Martin LU ; Ekedahl, Henrik LU ; Törngren, Therese LU ; Kvist, Anders LU ; Saal, Lao H LU ; Olsson, Håkan LU ; Staaf, Johan LU ; Carneiro, Ana LU and Ingvar, Christian LU , et al. (2017) In Molecular Oncology 11(4). p.438-451
Abstract

In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and... (More)

In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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Journal Article
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Molecular Oncology
volume
11
issue
4
pages
14 pages
publisher
Elsevier
external identifiers
  • wos:000405732700007
ISSN
1574-7891
DOI
10.1002/1878-0261.12050
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English
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yes
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6b4f03e3-c51c-4269-bb87-375c84d2e046
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2017-04-18 08:14:54
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2017-09-18 13:32:31
@article{6b4f03e3-c51c-4269-bb87-375c84d2e046,
  abstract     = {<p>In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.</p>},
  author       = {Cirenajwis, Helena and Lauss, Martin and Ekedahl, Henrik and Törngren, Therese and Kvist, Anders and Saal, Lao H and Olsson, Håkan and Staaf, Johan and Carneiro, Ana and Ingvar, Christian and Harbst, Katja and Hayward, Nicholas K and Jönsson, Göran B},
  issn         = {1574-7891},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {4},
  pages        = {438--451},
  publisher    = {Elsevier},
  series       = {Molecular Oncology},
  title        = {NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics},
  url          = {http://dx.doi.org/10.1002/1878-0261.12050},
  volume       = {11},
  year         = {2017},
}