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Research Paper|Volume 12, Issue 10|pp 9935—9947

Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1

Yu Ikemoto1,2, Toshiyuki Miyashita2, Michiyo Nasu1, Hiromi Hatsuse2, Kazuhiro Kajiwara1, Katsunori Fujii3, Toshino Motojima3, Ibuki Kokido1, Masashi Toyoda4, Akihiro Umezawa1
  • 1Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan
  • 2Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0374, Japan
  • 3Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
  • 4Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
Received: December 28, 2019Accepted: March 30, 2020Published: May 21, 2020
https://doi.org/10.18632/aging.103258

Copyright © 2020 Ikemoto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Gorlin syndrome is a rare autosomal dominant hereditary disease with a high incidence of tumors such as basal cell carcinoma and medulloblastoma. Disease-specific induced pluripotent stem cells (iPSCs) and an animal model have been used to analyze disease pathogenesis. In this study, we generated iPSCs derived from fibroblasts of four patients with Gorlin syndrome (Gln-iPSCs) with heterozygous mutations of the PTCH1 gene. Gln-iPSCs from the four patients developed into medulloblastoma, a manifestation of Gorlin syndrome, in 100% (four out of four), of teratomas after implantation into immunodeficient mice, but none (0/584) of the other iPSC-teratomas did so. One of the medulloblastomas showed loss of heterozygosity in the PTCH1 gene while the benign teratoma, i.e. the non-medulloblastoma portion, did not, indicating a close clinical correlation between tumorigenesis in Gorlin syndrome patients and Gln-iPSCs.