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.
Outcomes for melanoma patients with stage III disease differ widely even within the same subcategory.,Molecular signatures that more accurately predict prognosis are needed to stratify patients according to risk.,Proteomic analyses were used to identify differentially abundant proteins in extracts of surgically excised samples from patients with stage IIIc melanoma lymph node metastases.,Analysis of samples from patients with poor (n = 14, <1 yr) and good (n = 19, >4 yr) survival outcomes identified 84 proteins that were differentially abundant between prognostic groups.,Subsequent selected reaction monitoring analysis verified 21 proteins as potential biomarkers for survival.,Poor prognosis patients are characterized by increased levels of proteins involved in protein metabolism, nucleic acid metabolism, angiogenesis, deregulation of cellular energetics and methylation processes, and decreased levels of proteins involved in apoptosis and immune response.,These proteins are able to classify stage IIIc patients into prognostic subgroups (P < 0.02).,This is the first report of potential prognostic markers from stage III melanoma using proteomic analyses.,Validation of these protein markers in larger patient cohorts should define protein signatures that enable better stratification of stage III melanoma patients.