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Oncotarget. 2015 May 20;6(14):12297-309.

Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.

Author information

1
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
2
Department of Clinical Sciences, Division of Surgery, Lund University, Lund, Sweden.
3
Department of Oncology, Skåne University Hospital, Lund University, Lund, Sweden.
4
Department of Clinical Pathology, Skåne University Hospital, Lund University, Lund, Sweden.
5
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
6
Department of Dermatology, Helsingborg General Hospital, Helsingborg, Sweden.
7
Department of Dermatology, Harvard Medical School, Boston, USA.
8
Wellman Center for Photomedicine, MGH Cancer Center, Massachusetts General Hospital, Boston, USA.

Abstract

Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.

KEYWORDS:

BRAF; BRAF inhibitor; gene expression; melanoma; mutation

PMID:
25909218
PMCID:
PMC4494939
DOI:
10.18632/oncotarget.3655
[Indexed for MEDLINE]
Free PMC Article

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