Evaluation of Heterogeneity in the Coding Region of BRAF, MAP2K1, and MAP2K2 Genes in Primary and Metastatic Melanomas.

Introduction: The incidence of melanoma has been increasing in recent decades. BRAF mutations appear in 50%-70% of melanomas. The BRAF-targeted therapy increased the disease-free survival of patients with metastatic melanoma, but this response may be short, due to several resistance mechanisms, such as the presence of other subclones with mutations.

Molecular and immunological associations of elevated serum lactate dehydrogenase in metastatic melanoma patients: A fresh look at an old biomarker.

Elevated serum lactate dehydrogenase (sLDH) is associated with poor clinical outcomes in patients with stage IV metastatic melanoma (MM). It is currently unknown if sLDH elevation correlates with distinct molecular, metabolic, or immune features of melanoma metastases. The identification of such features may identify rational therapeutic strategies for patients with elevated sLDH.

IMP dehydrogenase rod/ring structures in acral melanomas.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells.

BRAFV600E and KIT immunoexpression in early-stage melanoma.

Melanoma is widely known as the most lethal skin cancer. Specific tumor-related mortality can be significantly reduced if diagnosis and treatment are properly performed during initial phases of the disease. The current search for biomarkers in early-stage melanomas is a high-priority challenge for physicians and researchers.

Intratumor Heterogeneity of KIT Gene Mutations in Acral Lentiginous Melanoma.

Melanoma is an aggressive skin malignancy, and the acral lentiginous melanoma (ALM) subtype affects non-sun-exposed sites such as the volar surface of the hands and feet and the subungual region and is most common in Asians, Hispanics, and Afro-descendants. The presence of different clones within the same tumor seems to influence the aggressiveness of tumors. Patients with mutations in the KIT gene have shown a good response to tyrosine kinase inhibitor therapy.

Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases.

There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival.

A Preexisting Rare Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in Melanoma and Is Dependent on S6K1 Signaling.

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with -mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired mutation as conferring drug resistance.