Molecular Profiling Reveals Low- and High-Grade Forms of Primary Melanoma

Abstract

Purpose For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome. Experimental Design We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data. Results Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84–8.59), and overall (HR = 3.66; 95% CI, 2.40–5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets. Conclusions We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.

Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma

“…Again supporting these RNA expression findings are the RPPA data showing on-treatment LCK antibody levels (an immune marker) to be among the most highly correlated with RECIST responses ( Figure 6I). Taken together, these observations suggest that tumors with primed immune systems might be better poised for response to treatment, consistent with a recent report on prognostic immune serum markers in a BRAF inhibitor trial (35) and with the observation that microarray-based immune infiltration signatures positively correlate with survival in non-BRAFi-treated melanoma patient populations (36)(37)(38)(39). Additionally, the large-scale TCGA (The Cancer Genome Atlas) study has confirmed that elevated lymphocytic RNA-seq signatures and LCK RPPA signals positively correlate with outcome in over 300 patients (https://tcga-data.…”

Immune Cell–Poor Melanomas Benefit from PD-1 Blockade after Targeted Type I IFN Activation

“…A bioinformatic analysis of genomewide transcriptomic data for 223 primary melanomas ( 23 ) indeed showed that the expression of CD3D and other T-cell transcripts directly correlated with the expression of a set of genes that are regulated by type I IFNs (Pearson correlation coeffi cient r = 0.6) in melanoma cells ( Fig. 1A and B and Supplementary Table S1).…”

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

“…Based on the molecular subtypes, a prognostic classifier was designed that divided primary melanomas into two groups (low and high grade). This prognostic classifier showed independent prognostic capacity in a multivariable model and was further validated in the Winnenpeninckx et al dataset [22]. Finally, the signature showed prognostic power in the more clinically challenging primary CMM (Breslow thickness >2 mm).…”

“…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].…”