Molecular characterization and natural history of linear porokeratosis: a case series
Here we employed immunohistochemistry and genetic testing by whole-exome or Sanger sequencing, to characterize six cases with linear porokeratosis (LP), all having negative family history for porokeratosis (Table 1). Histopathologically, cornoid lamellae were present in five patients. In two cases, the proximity to eccrine gland ducts led to misinterpretation of the diagnosis that was clarified by genetic testing. Porokeratosis was accompanied by increased proliferation of basal keratinocytes without evidence for increased apoptosis, and by an inflammatory infiltrate rich in CD4 and CD8 cells in three samples that were studied (Mendely Supplemental Fig. 1). The identified mutations, PMVK c.329G>A, p.R110Q and MVD c.70+5G>A have been reported before. In addition, we identified the unreported variant, MVK c.943_944del, p.L315Gfs*51. Second-hits led to loss-of-heterozygosity in LP. PMKV and MVK mutations were associated with verrucous and erythematous lesions, whereas, the MVD-associated LP were superficial and less inflammatory (Figure 1). Concerning the natural history, in all patients skin lesions grew and disseminated during childhood (Mendely Supplemental Fig. 2). At the age of 50 years, the oldest case in this series developed on the LP a squamous cell carcinoma (SCC) that was excised but recurred. Although only one LP-SCC was available for analysis, we analyzed its somatic mutations looking for insights into the drivers of carcinogenesis in LP. In the LP-SCC, 100 somatic mutations were identified and included the mutational signatures 7 (UV), 1 (“clock-like”) and 13 (AID/APOBEC family of cytidine deaminases) (Mendely Supplemental Fig. 3 and Tables). There were no typical mutations found in sporadic cutaneous SCC; the variant c.533C>T, p.L178S and a copy number gain were found in EP300, a gene reported to be genetically or epigenetically altered in various cancers.