Early-onset generalized linear porokeratosis with cutaneous squamous cell carcinomas: A case report and genomic analysis

Abstract

Previous studies have shown that porokeratosis (PK) arises from mutations in the enzyme-encoding genes – mevalonate kinase, phosphomevalonate kinase, mevalonate diphosphate decarboxylase ( MVD ), farnesyl diphosphate synthase, and farnesyl-diphosphate farnesyltransferase 1. This study reports a case of early-onset, generalized linear PK associated with cutaneous squamous cell carcinomas (cSCCs), focusing on the genetic context and molecular mechanisms underlying carcinogenesis. Paired skin specimens were collected from the proband and his father, along with blood samples from all four family members. Germline and somatic mutations were identified through whole-exome sequencing. To investigate the expression of the causative gene, we employed several approaches, including allelic expression imbalance assays, ribonucleic acid-seq, reverse transcription quantitative polymerase chain reaction, and immunohistochemistry. A germline NM_002461.1 ( MVD ): C.746T>C (p.Phe249Ser) mutation was identified in three family members. In the proband, a novel second-hit postzygotic mutation, NM_002461.1 ( MVD ): C.252_253dup (p.Glu85Glyfs*32), was detected in PK lesions. The proband’s cSCC exhibited both MVD : C.252_253dup (p.Glu85Glyfs*32) and a novel NM_000546.5 ( TP53 ): C.966_967del (p.Leu323Glyfs*13) somatic mutations, accompanied by significantly reduced MVD expression levels. Immunohistochemical analysis revealed a progressive decrease in MVD staining from adjacent normal-appearing skin to cSCC tissue. Transcriptomic analyses further revealed a downregulation of mevalonate pathway genes in cSCCs compared to matched controls. These findings highlight prenatal somatic mosaicism, leading to MVD deficiency in the epidermis, which may contribute to the development and carcinogenesis of linear PK.