Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit a germline mutation in genes encoding mevalonate pathway enzymes, MVD or MVK, in a heterozygous manner. Here, we showed that each skin lesion of DSAP and LP exhibited a second-hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postzygotic second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. We performed multiple biopsies of skin lesions and enzymatically separated the samples to the epidermis and dermis. Sanger sequencing and SNP array analyses revealed that, of 40 lesions biopsied from 7 DSAP patients, 26 lesional epidermal samples exhibited loss of heterozygosity of the congenital monoalleic mutation due to somatic homologous recombination rendering the monoallelic mutation biallelic. 10 lesional epidermal samples exhibited acquired mutations, principally C>T and CC>TT transitions or the complementary G>A and GG>AA transitions (8/10 acquired mutations). The second hits differed among lesions in each DSAP patient but were identical in each LP patient, suggesting that DSAP is attributable to sporadically-occurred postnatal second hits and LP to a single second hit in the embryonic period. In the characteristic annular skin lesions, the central epidermis featured mostly second-hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second-hit keratinocytes. Porokeratosis is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson’s two-hit hypothesis.

Keratinocyte specific biallelic mutations in mevalonate pathway genes due to postzygotic second hits drive linear and disseminated superficial actinic porokeratosis