RHBDF2 Mutations Are Associated with Tylosis, a Familial Esophageal 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 (Lead / Corresponding author)

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    112 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

    Cite this

    Blaydon, D. C., Etheridge, S. L., Risk, J. M., Hennies, H-C., Gay, L. J., Carroll, R., Plagnol, V., McRonald, F. E., Stevens, H. P., Spurr, N. K., Bishop, D. T., Ellis, A., Jankowski, J., Field, J. K., Leigh, I. M., South, A. P., & Kelsell, D. P. (2012). RHBDF2 Mutations Are Associated with Tylosis, a Familial Esophageal Cancer Syndrome. American Journal of Human Genetics, 90(2), 340-346. https://doi.org/10.1016/j.ajhg.2011.12.008