Melanoma, the most aggressive cutaneous cancer, metastasizes at very early stages of tumor development. Advances in treatment have produced therapies that target specific melanoma-associated mutations, as well as immune checkpoint blockade (ICB) therapies that strengthen patients’ anti-tumor immune response. Although these therapies allow drastic improvements in clinical outcomes for many patients, some patients exhibit melanomas with intrinsic or acquired resistance to these gene-based therapies. An article published in The Journal of Dermatology reviews melanoma classifications, genetic and phenotypic characteristics, and existing as well as emerging therapies.

Melanoma Subtypes

In 2018, the World Health Organization (WHO) changed melanoma classification from a solely anatomical basis to a clinical, histologic, epidemiologic, and genomic basis, and incorporating ultraviolet ray (UVR) exposure as well, describing 9 distinct “pathways” for the development of cutaneous, mucosal, and uveal melanomas with their potential precursor and simulant lesions. The most common WHO subtype in people with fair coloring is the low cumulative solar damage (CSD) melanoma, typically including superficial spreading melanoma (SSM), and the most common WHO melanoma subtype in people with darker coloring is the non-CSD melanoma, which includes acral melanoma (AM). Tumor mutation burden (TMB) is high in CSD melanomas and lower in non-CSD melanomas, with some exceptions, such as iris melanoma among the uveal melanoma (UM) subtype.

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Genetic Variations of Melanoma Subtypes

Sequencing technology allows genomic and molecular characterization of each melanoma subtype. For example, researchers know that cutaneous melanoma (CM) most often exhibits activating mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) and inactivating mutations in tumor suppressor gene neurofibromin 1 (NF1).

With whole exome sequencing (WES) and whole genome sequencing (WGS), researchers were able to identify significantly mutated genes (SMGs) in melanoma subtypes, which were used in The Cancer Genome Atlas (TCGA) to classify CM into 4 subtypes based on the pattern of the most prevalent SMGs. The study authors reviewed that melanoma tumors can also be differentiated based on their frequency of single-nucleotide variants (SNVs), indel, somatic structural variants, copy number variations, UV signature, and whole genome duplication (WGD).

In a study cited in the paper, investigators used array comparative genomic hybridization and targeted DNA and RNA sequencing to examine genomic features of spitzoid neoplasms, finding that these tumors frequently exhibit kinase fusions of ROS1, NTRK1, NTRK3, ALK, BRAF, RET, and MET in mutually exclusive patterns. Mouse experiments have shown an embryonic developmental origin shared among certain tumor cells, such as dermal and uveal melanocytes, shedding light on their genetic mutation similarities. Mutational signatures of UVR exposure are dominant in CM, conjunctival melanoma, and desmoplastic melanoma.

Gene Expression Profiling for Metastatic Risk and Phenotypic States

Gene expression profiling uses tumor phenotype to predict metastasis risk. For example, investigators developed a validated 12-gene microarray-based gene expression panel to establish 4 transcriptomic categories for UM tumors ranging from low-risk to high-risk prognoses. Gene expression profiling can also differentiate between proliferative and invasive transcriptomic phenotypes. In a study, genes in a proliferative melanoma phenotype were regulated by microphthalmia-associated transcription factors (MIFT) and SRY Transcription Factor 10 (SOX10), while genes in the invasive phenotype were regulated by transforming growth factor B (TGFB) signaling.

Research has shown that melanoma cells can reversibly shift between states, switching to more invasive phenotypes, known as phenotypic switching, the study authors noted. This can be influenced by extracellular factors, epigenetic factors, or even certain treatments such as has been shown with T-cell transfer therapy. They also cited studies that have shown that melanoma cells with different gene expression profiles can work in tandem to enhance survival. Most of the phenotypic switching literature is concerned with CM.

Melanoma Treatment: Gene Targeting and Drug Resistance

Current melanoma treatments focus on targeting functional effects of genetic alterations and immune checkpoint molecules, with a marked improvement in patient survival as a result. These include therapies against the mitogen-activated protein kinase (MAPK) signaling pathway using a combination of BRAF +/- mitogen-activated protein kinase kinase (MEK) inhibition, or ICB therapies using anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) and/or anti-programmed cell death protein 1 (PD1).

However, a major cause of therapeutic resistance is tumor heterogeneity at genetic and non-genetic (phenotypic and microenvironmental) levels. There are numerous known mechanisms of resistance to BRAF and MEK inhibitors including acquired mutations in genes of the MAPK pathay, and increasing evidence suggests non-genetic mechanisms for resistance as well. For ICB therapy, several models combine clinical, genomic and gene expression data to predict clinical outcomes. Therefore, the investigators wrote, the frontier in resistant melanoma therapy is targeted and ICB therapies that simultaneously suppress the drug-tolerant or resistant tumor cell populations. There are 2 distinct MITF-negative states that are highly de-differentiated and therefore resistant to targeted and IBC therapies.

Researchers are targeting these states concomitantly with standard melanoma therapies and have introduced several promising drugs such as a tyrosinase-processed antifolate prodrug TMECG and a drug-conjugated antibody against MITF-regulated melanosomal differentiation antigen GPNMB, the study authors concluded. More pre-clinical and clinical research is needed to hone the correct methods for drug combinations, doses, and administration schedule.


Oba J, Woodman SE. The genetic and epigenetic basis of distinct melanoma types. J Dermatol. Published online May 18, 2021. doi:10.1111/1346-8138.15957