Clinical, histopathologic, and molecular profiles of PRKAR1A-inactivated melanocytic neoplasms

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