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

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. 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.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. 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. Clin Cancer Res; 16(13); 3356-67. ©2010 AACR.Malignant melanoma is an aggressive form of skin cancer with a rapidly increasing incidence in the western world (1). Approximately 15% of patients diagnosed with primary melanoma develop distant metastases (2), and current treatment regimens for metastatic melanoma have little effect on long-term survival. Single agent dacarbazine (DTIC) has been standard treatment for many years with response rates of 7% to 13%; however, long-lasting responses are few (3). Importantly, several novel treatment approaches, systemic and targeted, are emerging (4). The concept and arguments for immunotherapy in melanoma include reports on spontaneous remissions and lymphocytic infiltration in tumors (5). However, a rationale for selecting patients eligible for immunotherapy is still lacking.Although there have been several reports on gene expression signatures in malignant melanomas (6-8), only few studies have indicated molecular subtypes of clinical relevance in metastatic melanoma (7, 9). In primary melanoma, genetic profiles are correlated to anatomic site

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

“…A trend to significance was observed for age at diagnosis and the UV signature ( P  =   0.02, Kruskal–Wallis test); however, after correction for multiple testing, significance was lost. Next, we determined the association between mutational signatures and mutational groups or gene expression subtypes as described previously (Jonsson et al ., 2010). Tumors belonging to the BRAF hotspot‐mutant group had significantly lower association with the UV mutational signature, while NF1 ‐mutant tumors had stronger association with the UV signature ( P  <   0.001, Kruskal–Wallis test), although we did not detect any difference with regard to gene expression subtypes (Fig.…”

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

“…63 The melanoma survival rate was directly analyzed using the other GEO data set (GSE22153). 64 Xenograft study. Approximately 2 × 10 6 HCT116 or 1 × 10 6 UACC-62 stable cells expressing shGFP or shUSP11 were resuspended in 50 μl PBS and 50 μl Matrigel matrix (354234, BD Biosciences, Franklin Lakes, NJ, USA) and subcutaneously inoculated into 6-week-old female Balb/c nude mice (Narabiotech, Korea).…”

Advances in molecular profiling of malignant melanoma: ready for clinical practice?

“…In contrast, several groups have analyzed GEX profiles from metastatic CMM [15][16][17][18]. A distinct common denominator in these studies is the finding that elevated expression of immune response-related genes is associated with improved outcome.…”

“…In an attempt to define molecular subtypes analogous to the more established breast cancer GEX subtypes used in clinical practice [19], we used unsupervised analysis of tumors from 57 metastatic CMM [17]. Importantly, this cohort consisted of stage IV patients enrolled in a clinical trial investigating the effect of dacarbizine (DTIC).…”

“…Notably, based on the results from these two studies [17,22] only 7% of primary melanomas were classified as proliferative, while in the stage IV melanomas 21% were proliferative, suggesting that the distribution of subtypes is dependent on disease stage. More recently, we have also observed that multiple metastases from the same patient can be of different molecular subtype [23].…”