Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Akiharu Kubo, Takashi Sasaki, Hisato Suzuki, Aiko Shiohama, Satomi Aoki, Showbu Sato, Harumi Fujita, Noriko Ono, Noriko Umegaki-Arao, Tomoko Kawai, Kazuhiko Nakabayashi, Kenichiro Hata, Daisuke Yamada, Yoichi Matsubara, Kenjiro Kosaki, Masayuki Amagai

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3 Citations (Scopus)

Abstract

Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as 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, either 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 LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP 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 naïve 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.

Original languageEnglish
Pages (from-to)2458-2466.e9
JournalJournal of Investigative Dermatology
Volume139
Issue number12
DOIs
Publication statusPublished - 2019 Dec

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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    Kubo, A., Sasaki, T., Suzuki, H., Shiohama, A., Aoki, S., Sato, S., Fujita, H., Ono, N., Umegaki-Arao, N., Kawai, T., Nakabayashi, K., Hata, K., Yamada, D., Matsubara, Y., Kosaki, K., & Amagai, M. (2019). Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes. Journal of Investigative Dermatology, 139(12), 2458-2466.e9. https://doi.org/10.1016/j.jid.2019.05.020