Clinical, histopathologic, and molecular profiles of PRKAR1A-inactivated melanocytic neoplasms
Authors: Erik A. Williams, Nikunj Shah, Natalie Danziger, Meagan Montesion, Ethan S. Sokol, Dean C. Pavlick, Vincent A. Miller, Jeffrey S. Ross, Julia A. Elvin, Julie Y. Tse
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Protein kinase A regulatory subunit-α (PRKAR1A) is inactivated in a subset of melanocytic neoplasms, including pigmented epithelioid melanocytoma (PEM), melanotic schwannoma (MS), and the exceptionally rare pigmented epithelioid melanoma.1Wang L. Zehir A. Sadowska J. et al.Consistent copy number changes and recurrent PRKAR1A mutations distinguish melanotic schwannomas from melanomas: SNP-array and next generation sequencing analysis.Genes Chromosomes Cancer. 2015; 54: 463-471Crossref PubMed Scopus (23) Google Scholar,2Cohen J.N. Spies J.A. Ross F. Bohlke A. McCalmont T.H. Heavily pigmented epithelioid melanoma with loss of protein kinase A regulatory subunit-α expression.Am J Dermatopathol. 2018; 40: 912-916Crossref PubMed Scopus (10) Google Scholar The genomic profiles of PEM and MS have been well described; PEM typically lacks genomic alterations (GAs) in the TERT promoter or CDKN2A gene or significant chromosomal copy number alterations, whereas MS shows monosomies of chromosomes 1, 2, and 17. Cohen et al2Cohen J.N. Spies J.A. Ross F. Bohlke A. McCalmont T.H. Heavily pigmented epithelioid melanoma with loss of protein kinase A regulatory subunit-α expression.Am J Dermatopathol. 2018; 40: 912-916Crossref PubMed Scopus (10) Google Scholar recently described histopathologic findings of a single case of heavily pigmented epithelioid melanoma with loss of PRKAR1A expression.2Cohen J.N. Spies J.A. Ross F. Bohlke A. McCalmont T.H. Heavily pigmented epithelioid melanoma with loss of protein kinase A regulatory subunit-α expression.Am J Dermatopathol. 2018; 40: 912-916Crossref PubMed Scopus (10) Google Scholar Here, we used comprehensive genomic profiling (CGP) to identify the characteristics of PRKAR1A-inactivated melanomas. We searched our archive of 255,008 clinical samples that had undergone CGP using a hybrid capture-based DNA sequencing platform3Frampton G.M. Fichtenholtz A. Otto G.A. et al.Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.Nat Biotechnol. 2013; 31: 1023-1031Crossref PubMed Scopus (1276) Google Scholar for melanocytic neoplasms with inactivating GAs in PRKAR1A. Approval for this study, including a waiver of informed consent and a Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board (protocol no. 20152817). Inactivating PRKAR1A GAs were detected in 42 of 4770 melanocytic neoplasms (0.9%). Of these, 34 cases were melanoma (primary sites: 32 nonacral cutaneous, 1 acral, and 1 anal mucosal), 6 were MS, and 2 were melanocytomas. Disease classifications were based on diagnoses submitted by the clinician, pathology reports, histology, and GAs. Cases showed truncating variants (n = 29), splice-site variants (n = 8), and homozygous deletions (n = 5) in PRKAR1A. In the melanoma cohort, median age was 59 years (range, 18-87 y), 68% were male, and 94% had documented advanced disease. Specimen sites included primary sites (n = 9), regional lymph nodes (n = 7), and distant metastases (n = 18). Overall, 94% of melanomas harbored a pathogenic GA in TERTp, CDKN2A, or both; 50% were BRAF mutant (10/17 were BRAF V600E), 28% were NRAS mutant, 18% were NF1 mutant, and 18% were triple wild type (Fig 1). Genomic profiles showed no significant differences between primary and metastatic sites. Among melanomas, the median tumor mutational burden was 15.0 mutations/megabase (range, 1.7-187 mut/Mb). PD-L1 tumor immunohistochemistry was performed on 9 melanoma cases, with positive staining (>1%) identified in 3 cases (33%), similar to the 31.3% rate of PD-L1 positivity in all melanomas in the CGP database. Half (15/30) of the melanomas with available histology showed large epithelioid and dendritic melanocytes with prominent nucleoli, gray-blue cytoplasm, and abundant melanin pigment, arranged in large confluent nests and fascicles, consistent with features described in PEM (Fig 2). Melanomas sequenced from primary tumors or regional lymph nodes showed a significant correlation with PEM-like histology compared with those sequenced from distant metastasis (73% vs 27%, P = .027). The remaining cases showed unremarkable smaller epithelioid and/or fusiform cells with no consistent architecture. Inactivation of PRKAR1A is known to increase cyclic adenosine monophosphate–stimulated protein kinase A activity and has been shown to promote tumorigenesis and modulate the tumor microenvironment.4Codina A. Renauer P.A. Wang G. et al.Convergent identification and interrogation of tumor-intrinsic factors that modulate cancer immunity in vivo.Cell Syst. 2019; 8: 136-151Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Preclinical data have shown possible targeted treatment strategies.5Sapio L. Di Maiolo F. Illiano M. et al.Targeting protein kinase A in cancer therapy: an update.EXCLI J. 2014; 13: 843-855PubMed Google Scholar Although the current study is limited by its retrospective nature, enrichment for clinically advanced tumors, and the lack of follow-up data and patient-paired primary/metastatic tumor analysis, our findings suggest the need for further investigational studies to assess the outcomes of PRKAR1A-inactivated melanomas, including possible stratification of patients for personalized therapeutic options.