Somatic mosaicism containing double mutations in<i>PTCH1</i>revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome

Ikemoto, Yu; Takayama, Yoshinaga; Fujii, Kiyotaka; Masuda, Mokuri; Kato, Chise; Hatsuse, Hiromi; Fujitani, Kazuko; Nagao, Keiko; Kameyama, Kohzoh; Ikehara, Hajime; Toyoda, Masashi; Umezawa, Akihiro; Miyashita, Toshiyuki

doi:10.1136/jmedgenet-2016-104490

Cited by 13 publications

(16 citation statements)

References 19 publications

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“…We investigated whether there were any genotype–phenotype relationships with PTCH1 mutations by gene domains or mutation type. Consistent with previous reports (Evans et al, ; Ikemoto et al, ; Kato et al, ; Okamoto et al, ), we found no hot spots or strong genotype–phenotype relationships. There was a suggestive association between falx cerebri calcifications and all transmembrane domains, although not statistically significant using a more conservative Bonferroni correction for multiple comparison.…”

Section: Discussionsupporting

confidence: 93%

“…Extracellular 1 and extracellular 4 domains have been suggested to be important for SHH binding (Marigo, Davey, Zuo, Cunningham, & Tabin, 1996). However, pathogenic mutations are rarely shared among unrelated families, and no specific hot spots or genotype-phenotype correlations have been identified (Evans et al, 2017;Ikemoto et al, 2017;Kato et al, 2017;Okamoto, Naruto, Kohmoto, Komori, & Imoto, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Gianferante

Rotunno

Dean

et al. 2018

Molec Gen & Gen Med

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BackgroundNevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype–phenotype relationships.MethodsWe evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease‐causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype–phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains.Results PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation‐negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype–phenotype association was observed for developmental delay and gross deletion–insertions (p = 9.0 × 10−6), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion–insertions (p = 4.0 × 10−4).ConclusionOverall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation‐negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow‐up and future studies of genotype–phenotype relationships.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Gianferante

Rotunno

Dean

et al. 2018

Molec Gen & Gen Med

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“…As described above, the high incidence of biallelic somatic PTCH1 mutation is quite high in KCOT (80% of the cases), and somatic PTCH1 mutation seems to be quite characteristic of this disease. However, such somatic mutations have also been reported as mosaic mutations in GS [ 30 , 31 ]. Other rare causative genes such as SUFU and PTCH2 genes have also been detected in GS.…”

Section: Genetic and Molecular Structural Aspects Of Gorlin Syndromentioning

confidence: 99%

“…Patient-derived hiPSCs are also used for in vitro disease modeling and drug screening. Recently, iPSCs derived from patients with GS have been reported by several groups [ 31 , 48 , 117 , 118 , 119 , 120 ]. By using iPSCs derived from patients with GS, a model of abnormal tissue development and tumor formation can be constructed.…”

Section: Disease-specific Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

Onodera

Nakamura

2020

IJMS

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Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.

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“…Moreover, Gln-iPSCs may serve a model to elucidate mechanism for LOH of the PTCH1 gene in patients with Gorlin syndrome. Odontogenic keratocysts of the jaw, palmar pits, calcification of falx cerebri, stomach cancer *1: Patient "G72" had a germline mutation, c.272delG, and a low prevalence of somatic mutation, c.274delT, that was derived from the allele with a germline mutation, but not from the wild-type allele (25). B. Medulloblastomas were generated in the teratomas by Gln-iPSCs (G11, G12, G36, G72).…”

Section: Acceleration Of Hh Signaling In Correlation With Ipsc Generamentioning

confidence: 99%

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

Ikemoto

Miyashita

Nasu

et al. 2019

Preprint

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

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Somatic mosaicism containing double mutations inPTCH1revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome

Cited by 13 publications

References 19 publications

Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Whole‐exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

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

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