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Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome.

Jönsson, Göran B LU ; Busch, Christian; Knappskog, Stian; Geisler, Jürgen; Miletic, Hrvoje; Ringnér, Markus LU ; Lillehaug, Johan R; Borg, Åke LU and Lonning, Per Eystein (2010) In Clinical Cancer Research 16(13). p.3356-3367
Abstract
PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed... (More)
PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation or stromal composition genes. Even though all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (p<0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by high frequency of CDKN2A homozygous deletions (p<0.01). We observed different prognosis between the subtypes (p=0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared to the others (p = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III/IV melanomas. Moreover, low expression of an a priori-defined gene set associated to immune response signaling was significantly associated to poor outcome (p=0.001). CONCLUSIONS: Our data reveal a biologically-based taxonomy of malignant melanomas with prognostic impact and support an influence of the anti-tumoral immune response on outcome. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
16
issue
13
pages
3356 - 3367
publisher
American Association for Cancer Research
external identifiers
  • wos:000279399200008
  • pmid:20460471
  • scopus:77954234849
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-09-2509
project
CREATE Health
language
English
LU publication?
yes
id
37e71fed-f024-4d76-9516-f95e47b82405 (old id 1610301)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20460471?dopt=Abstract
date added to LUP
2010-06-02 10:33:01
date last changed
2018-06-24 04:48:20
@article{37e71fed-f024-4d76-9516-f95e47b82405,
  abstract     = {PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation or stromal composition genes. Even though all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (p&lt;0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by high frequency of CDKN2A homozygous deletions (p&lt;0.01). We observed different prognosis between the subtypes (p=0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared to the others (p = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III/IV melanomas. Moreover, low expression of an a priori-defined gene set associated to immune response signaling was significantly associated to poor outcome (p=0.001). CONCLUSIONS: Our data reveal a biologically-based taxonomy of malignant melanomas with prognostic impact and support an influence of the anti-tumoral immune response on outcome.},
  author       = {Jönsson, Göran B and Busch, Christian and Knappskog, Stian and Geisler, Jürgen and Miletic, Hrvoje and Ringnér, Markus and Lillehaug, Johan R and Borg, Åke and Lonning, Per Eystein},
  issn         = {1078-0432},
  language     = {eng},
  number       = {13},
  pages        = {3356--3367},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-09-2509},
  volume       = {16},
  year         = {2010},
}