Genomic Analysis of Pigmented Epithelioid Melanocytomas Reveals Recurrent Alterations in PRKAR1A, and PRKCA Genes

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Abstract

Pigmented epithelioid melanocytoma (PEM) is a rare cutaneous melanocytic tumor first described as epithelioid blue nevus in patients with the Carney Complex (CC). PEM was among the first established examples of an intermediate class of melanocytic tumors, including atypical Spitz tumors, with frequent metastasis to lymph nodes but only rare extranodal spread. Sporadic and CC-associated PEM are essentially histologically indistinguishable. A subset of PEM shows loss of cytoplasmic expression of the protein kinase A regulatory subunit alpha (PRKAR1A), a tumor suppressor gene mutated in 70% of families with CC. However, molecular studies of such tumors have been limited. Therefore, we used next-generation sequencing to assess 480 cancer-related genes and performed PrkaR1α immunohistochemistry on 13 cases morphologically consistent with PEM. Six cases demonstrated loss of PrkaR1α expression by immunohistochemistry. Three cases were “combined” PEM arising in association with a common nevus. These lesions harbored PRKAR1A genetic alterations in addition to BRAF mutations. Three “pure” PEM, not associated with a common nevus, showed no evidence of PRKAR1A genetic alterations despite loss of PrkaR1α expression. Two of these PEM demonstrated MAP2K1 in frame deletions. PrkaR1α protein expression was preserved in 7 cases. Two of these lesions revealed fusions of the gene encoding the protein kinase C alpha isoform (PRKCA) to 2 distinct partners (ATP2B4-PRKCA and RNF13-PRKCA). Two lesions may represent misdiagnosed “blue nevus with epithelioid features” as they demonstrated GNAQ hotspot mutations. A conceivable explanation, but one we do not favor is that rare PEM are caused by GNAQ mutations. No genetic aberrations were detected in 3 lesions. None of our 13 cases demonstrated TERT alterations or significant chromosomal copy number changes. These results further validate the concept of PEM as a distinctive intermediate/borderline melanocytic tumor, and also illustrate its molecular heterogeneity.

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