RHBDF2 Mutations are Associated with Tylosis, a Familial Esophagel Cancer Syndrome

Diana C Blaydon, Sarah L Etheridge, Janet M Risk, Hans-Christian Hennies, Laura J Gay, Rebecca Carroll, Vincent Plagnol, Fiona E McRonald, Howard P Stevens, Nigel K Spurr, D Timothy Bishop, Anthony Ellis, Janusz Jankowski, John K Field, Irene M Leigh, Andrew P South, David P Kelsell

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

Original languageEnglish
Pages (from-to)340-346
Number of pages7
JournalAmerican Journal of Human Genetics
Volume90
Issue number2
DOIs
Publication statusPublished - 10 Feb 2012
Externally publishedYes

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Esophageal Neoplasms
Keratoderma, Palmoplantar, Diffuse
Mutation
Neoplasms
Epidermal Growth Factor Receptor
Palmoplantar Keratoderma
Skin
Missense Mutation
Keratinocytes
Epidermal Growth Factor
Squamous Cell Carcinoma
Intercellular Signaling Peptides and Proteins
Peptide Hydrolases
Hyperkeratosis of the palms and soles and esophageal papillomas
Drug Therapy

Cite this

Blaydon, D. C., Etheridge, S. L., Risk, J. M., Hennies, H-C., Gay, L. J., Carroll, R., ... Kelsell, D. P. (2012). RHBDF2 Mutations are Associated with Tylosis, a Familial Esophagel Cancer Syndrome. American Journal of Human Genetics, 90(2), 340-346. https://doi.org/10.1016/j.ajhg.2011.12.008
Blaydon, Diana C ; Etheridge, Sarah L ; Risk, Janet M ; Hennies, Hans-Christian ; Gay, Laura J ; Carroll, Rebecca ; Plagnol, Vincent ; McRonald, Fiona E ; Stevens, Howard P ; Spurr, Nigel K ; Bishop, D Timothy ; Ellis, Anthony ; Jankowski, Janusz ; Field, John K ; Leigh, Irene M ; South, Andrew P ; Kelsell, David P. / RHBDF2 Mutations are Associated with Tylosis, a Familial Esophagel Cancer Syndrome. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 2. pp. 340-346.
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abstract = "Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.",
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Blaydon, DC, Etheridge, SL, Risk, JM, Hennies, H-C, Gay, LJ, Carroll, R, Plagnol, V, McRonald, FE, Stevens, HP, Spurr, NK, Bishop, DT, Ellis, A, Jankowski, J, Field, JK, Leigh, IM, South, AP & Kelsell, DP 2012, 'RHBDF2 Mutations are Associated with Tylosis, a Familial Esophagel Cancer Syndrome', American Journal of Human Genetics, vol. 90, no. 2, pp. 340-346. https://doi.org/10.1016/j.ajhg.2011.12.008

RHBDF2 Mutations are Associated with Tylosis, a Familial Esophagel Cancer Syndrome. / Blaydon, Diana C; Etheridge, Sarah L; Risk, Janet M; Hennies, Hans-Christian; Gay, Laura J; Carroll, Rebecca; Plagnol, Vincent; McRonald, Fiona E; Stevens, Howard P; Spurr, Nigel K; Bishop, D Timothy; Ellis, Anthony; Jankowski, Janusz; Field, John K; Leigh, Irene M; South, Andrew P; Kelsell, David P.

In: American Journal of Human Genetics, Vol. 90, No. 2, 10.02.2012, p. 340-346.

Research output: Contribution to journalArticle

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T1 - RHBDF2 Mutations are Associated with Tylosis, a Familial Esophagel Cancer Syndrome

AU - Blaydon, Diana C

AU - Etheridge, Sarah L

AU - Risk, Janet M

AU - Hennies, Hans-Christian

AU - Gay, Laura J

AU - Carroll, Rebecca

AU - Plagnol, Vincent

AU - McRonald, Fiona E

AU - Stevens, Howard P

AU - Spurr, Nigel K

AU - Bishop, D Timothy

AU - Ellis, Anthony

AU - Jankowski, Janusz

AU - Field, John K

AU - Leigh, Irene M

AU - South, Andrew P

AU - Kelsell, David P

N1 - Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2012/2/10

Y1 - 2012/2/10

N2 - Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

AB - Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

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KW - Exons

KW - Humans

KW - Keratinocytes

KW - Keratoderma, Palmoplantar, Diffuse

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Pedigree

KW - Phenotype

KW - Receptor, Epidermal Growth Factor

KW - Sequence Alignment

KW - Serine Proteases

KW - Untranslated Regions

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

UR - http://www.cell.com/ajhg/home

U2 - 10.1016/j.ajhg.2011.12.008

DO - 10.1016/j.ajhg.2011.12.008

M3 - Article

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EP - 346

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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