Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes

Abstract Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, MVD or MVK . Here, we showed that each skin lesion of DSAP exhibited an individual second-hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, i.e., somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele. The second hits differed among DSAP lesions but were identical in those of congenital linear porokeratosis, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital linear porokeratosis to a single second hit in the embryonic period. In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second-hit keratinocytes, and that of the annular ring featured a mixture of such cells and naive keratinocytes, implying that each lesion reflects the clonal expansion of single second-hit keratinocytes. DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis.