Gene expression profiling-based identification of molecular subtypes in stage IV melanomas with different clinical outcome.
OBJECTIVE
The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.


METHODS
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. Although 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 a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).


CONCLUSIONS
Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome.
Jönsson
Göran
G
Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
Busch
Christian
C
Knappskog
Stian
S
Geisler
Jürgen
J
Miletic
Hrvoje
H
Ringnér
Markus
M
Lillehaug
Johan R
JR
Borg
Ake
A
Lønning
Per Eystein
PE
D056915:DNA Copy Number Variations; D017353:Gene Deletion; D020869:Gene Expression Profiling; D019942:Genes, p16; D006801:Humans; D008545:Melanoma / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D054928:Validation Studies as Topic
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf