Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1

Abstract

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma–like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars1,2. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome–related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.

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Figure 1: Mutations in TGFBR1 in individuals with MSSE.
Figure 2: Expression of TGFβRI protein in MSSE tumors.
Figure 3: Loss of heterozygosity in a TGFBR1 c.806-2A>C tumor with retention of the mutant allele.
Figure 4: In silico modeling of the extracellular domain of the TGF-β signaling complex to illustrate the impact of the MSSE mutations in exon 2.
Figure 5: Effect of alterations to the extracellular domain of TGFβRI on TGF-β signaling through SMAD2/3.

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GenBank/EMBL/DDBJ

NCBI Reference Sequence

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Acknowledgements

This work was supported by Cancer Research UK (grants C26/A4049 to E.B.L. and D.R.G.; C26/A1461, C26/A6694 and C26/A11657 to E.B.L.) and the Biomedical Research Council (A*STAR) of Singapore. We thank the University of California Los Angeles Genomic Sequencing Center for providing access to next-generation sequencing, alignment and variant calling computational systems; F. Richards for tumor DNA; R. Barlow for subject referral; A. Cassidy for help with sequencing and the TaqMan assay; D. Baty for access to the resources of his laboratory and many individuals with MSSE for their help.

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D.R.G. and E.B.L. initiated the project. D.R.G., M.A.F.-S., G.P., A.-M.G., S.B.-O., J.F., I.H., N.B. and S.W. identified, ascertained and took samples from subjects' families. E.B.L., M.D., D.R.G. and B.R. designed strategies, supervised and implemented the project. B.M., H.L., B.D.O. and S.F.N. designed and performed re-analysis of linkage data, array capture reagents, high-throughput sequencing and data analysis and interpretation. M.D. and S.E.C. performed the dideoxy sequencing. D.R.G., L.C. and A.S. performed the loss of heterozygosity (LOH) studies. D.R.G. performed the linkage and haplotype analysis of the discovered variants. I.S., B.R. and S.A. performed the functional assays. D.P.L. performed the immunohistochemistry. C.V. carried out the structural modeling. E.B.L., D.R.G., M.D. and I.S. wrote the paper with contributions from the other authors.

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Correspondence to E Birgitte Lane.

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The authors declare no competing financial interests.

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Goudie, D., D'Alessandro, M., Merriman, B. et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nat Genet 43, 365–369 (2011). https://doi.org/10.1038/ng.780

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