Track

Clinical Studies

Abstract

Mutations in the tumor suppressor protein kinase A (PKA) regulatory subunit 1 alpha (PRKAR1A) are often found in the intermediate-grade pigmented epithelioid melanocytoma (PEM), showing significant histopathologic overlap with melanoma. However, the role of PRKAR1A in melanoma continues to be underexplored. We searched our database of over 3,300 melanomas (all histologies), which had undergone targeted next generation sequencing. We identified 30 cases from 28 unique patients with mutations in PRKAR1A. Cutaneous melanoma represented most cases (22/28, 78.5%), followed by unknown primary (5/28, 17.8%) and mucosal vulvar (1/28, 3.6%). The mean age was 66.2 years (32-96yrs). Males predominated (17/27, 60.7%) as well as metastases (21/29, 72.4%). 18 patients were alive (18/27, 66.7%) and 9 had died (9/27, 33.3%) at up to 95.2 months with no significant difference in mortality outcomes (P-value = 0.671). The mean Breslow depth was 4.8 mm (16 cases, 0.32-13.3 mm) and mean number of mitoses was 8.6 per mm² (1-30 mites). Approximately half (13/28, 46.4%) of melanomas with available histology showed features described in PEM. The PRKAR1A mutations identified were largely missense (20/27, 74.1%), truncating (5/27, 18.5%), and splice site (2/27, 7.4%). PRKAR1A-mutated melanomas were statistically more likely to have alterations in TERT (24/28, 85.7%), KMT2D and KMT2B (15/28, 53.6%; 12/24, 50%), TP53 (13/28, 46.4%), and TSC1 (7/28, 25%). BRAF, CDKN2A, and NRAS mutations were not significantly differentially enriched. Taken together, there were histologic and molecular genetic differences identified, with potential treatment implications, especially in the setting of TSC-related therapies.