Abstract
We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a Tcell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
Highlights
Vating mutations for patients with unresectable disease and/or distant melanoma metastases can be identified through genetic analyses
Diagnosis and surgical resection of early-stage primary cutaneous melanoma is often curative for patients with localized disease, but the prognosis is less favorable for patients with regional metastases
Multi-dimensional Genomic Characterization of Cutaneous Melanoma Compared to most solid tumors, primary melanomas are generally small at diagnosis; and in routine clinical practice, most or all of primary tumor tissue is used for diagnostic evaluation and is not available for molecular analyses
Summary
Diagnosis and surgical resection of early-stage primary cutaneous melanoma is often curative for patients with localized disease, but the prognosis is less favorable for patients with regional metastases. Using the technique of lymphatic mapping and sentinel lymph node (SLN) biopsy (Gershenwald and Ross, 2011), early surgical intervention for patients with microscopic regional lymph node metastases (i.e., positive SLNs) has recently been found useful for prognosis, may improve survival in a subgroup of such patients, and serves to guide the use of adjuvant therapy (Morton et al, 2014). Hot-spot mutations in the V600 codon of BRAF (35%–50% of melanomas) and Q61 codons (less frequently, the G12 or G13 codon) of NRAS (10%–25%) led to the development of highly selective kinase inhibitors that target the MAPK pathway (Tsao et al, 2012). Recent clinical trials have provided proof of principle that therapeutic agents targeting acti-
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