Unveiling Cellular Identities and Gene Expression Pathways in Overlapping Myocarditis and Myositis.

Immune checkpoint therapies can drive antitumor responses and benefit patients but can also induce life-threatening immune-related adverse events such as myocarditis and myositis. These immune-related adverse events are rare but carry substantial morbidity and mortality. In this issue, Siddiqui and colleagues use single-cell RNA and T-cell receptor sequencing to identify novel cellular subsets and propose various mechanisms that could contribute to the pathogenesis of immune checkpoint inhibitor-associated myocarditis and myositis. These new insights should help move the field toward the development of improved treatment and prevention options, ultimately improving patient outcomes. See related article by Siddiqui et al., p. 964 (1).

Genetic analysis of multiple primary melanomas arising within the boundaries of congenital nevi depigmentosa.

Here, we present a rare case of a patient who developed multiple primary melanomas within the boundaries of two nevi depigmentosa. The melanomas were excised, and as a preventive measure, the remainder of the nevi depigmentosa were removed. We performed whole-exome sequencing on excised tissue from the nevus depigmentosus, adjacent normal skin, and saliva to explain this intriguing phenomenon. We also performed a GeneTrails Comprehensive Solid Tumor Panel analysis on one of the melanoma tissues. Genetic analysis revealed germline MC1R V92M and TYR R402Q polymorphisms and a MET E168D germline mutation that may have increased the risk of melanoma development. This genetic predisposition, combined with a patient-reported history of substantial sun exposure and sunburns, which were more severe within the boundaries of the nevi depigmentosa due to the lack of photoprotective melanin, produced numerous somatic mutations in the melanocytes of the nevi depigmentosa. Fitting with this paradigm for melanoma development in chronically sun-damaged skin, the patient's melanomas harbored somatic mutations in CDKN2A (splice site), NF1, and ATRX and had a tumor mutation burden in the 90-95th percentile for melanoma.