Melanoma genomics: a state‐of‐the‐art review of practical clinical applications*

Abstract

Summary Our collective understanding of melanoma genomics has rapidly expanded in the past decade, bringing great promise to patients affected with the most severe and aggressive cases of melanoma. In this review, we present the practical clinical impact of genetics and genomics on modern melanoma diagnosis and treatment. Characterization of somatic driver mutations, which can be used to distinguish different subtypes of melanoma such as nonacral cutaneous melanoma (NACM), desmoplastic melanoma (DM), acral melanoma (AM), mucosal melanoma (MM) and uveal melanoma (UM), has led to the development of many targeted therapies against these tumours. Although targeted therapies exist for certain mutations, such as BRAF and KIT, other genotypes respond to newer‐generation immune therapies such as immune checkpoint inhibitors. Epigenetics also plays a critical role in melanoma pathogenesis and drug resistance, holding promise for new treatment avenues. In this review, special attention is placed on clinical trials and translational research, especially novel genomic tests aimed to benefit patients on an individualized level in the current emerging era of personalized therapy.

A review of nevus‐associated melanoma: What is the evidence?

“…The BRAF gene encodes a serine/threonine kinase, which plays a critical role in the mitogen‐activated protein kinase (MAPK) signalling pathway regulating cell survival, differentiation and proliferation 64 . BRAF mutations (80% of which are V600E mutations, with a valine to glutamic acid substitution) occur in approximately 60% of melanomas.…”

“…The BRAF gene encodes a serine/threonine kinase, which plays a critical role in the mitogen-activated protein kinase (MAPK) signalling pathway regulating cell survival, differentiation and proliferation. 64 BRAF mutations (80% of which are V600E mutations, with a valine to glutamic acid substitution) occur in approximately 60% of melanomas. Also, 82% of benign nevi also harbour the BRAFV600E mutation, suggesting that this mutation is insufficient to transform human melanocytes to melanoma by itself, and additional genetic and molecular events are required to act in concert.…”

“…Also, 82% of benign nevi also harbour the BRAFV600E mutation, suggesting that this mutation is insufficient to transform human melanocytes to melanoma by itself, and additional genetic and molecular events are required to act in concert. 64,65 The mutations related to melanocytic nevi are outside the scope of this article and have been presented elsewhere. 66,67 There are reports for a role of the BRAFV600E mutation in the development of NAM compared to de novo melanoma.…”

Loss of ‘Epidermal Melanin Unit’ Integrity in Human Skin During Melanoma-Genesis

“…While exposure to ultraviolet radiation (UVR) constitutes the major risk factor for cutaneous melanoma, and sun-protected melanocytes exhibit fewer mutations than sun-exposed ones, pigment cells from chronically sun-exposed skin (e.g., face) carry a lower mutational burden than melanocytes from intermittently-exposed skin (e.g., back). Thus, tumor progression is facilitated by a combination of genetic and epigenetic modifications, and people with pale skin, freckles, and red (pheomelanin-rich) hair exhibit the highest risk of melanocyte malignant transformation ( 12 , 13 ). In addition to (epi)genetic characteristics, factors in the melanocyte microenvironment also modulate the oncogenic process e.g., extracellular matrix (ECM), microvasculature, intercellular communication (melanocyte-keratinocyte-fibroblast), as well as alterations in growth factors, cytokines, and nutrients.…”

Cholecystokinin Receptor Antagonist Suppresses Melanoma Growth by Inducing Apoptosis of Tumor Cells

“…Recently, large-scale genomic profiling identified considerable heterogeneity in melanoma. Characterization of somatic driver sequence variants can be used to distinguish between different subtypes of melanoma, such as nonacral cutaneous melanoma, desmoplastic melanoma, acral melanoma, mucosal melanoma, and uveal melanoma, leading to the development of many targeted therapies against tumors ( Guhan et al., 2021 ). Although targeted therapies exist for certain sequence variants, such as BRAF and KIT , other genotypes respond to newer-generation immune therapies.…”