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RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome

Blaydon, D.C., Etheridge, S.L., Risk, J.M., Hennies, Hans 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. and Kelsell, D.P. (2012) RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. The American Journal of Human Genetics, 90 (2). pp. 340-346. ISSN 0002-9297

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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.

Item Type: Article
Additional Information: Unmapped bibliographic data: ST - RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome [Field not mapped to EPrints] C2 - PMC3276661 [Field not mapped to EPrints] AD - Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. [Field not mapped to EPrints] AN - 22265016 [Field not mapped to EPrints]
Uncontrolled Keywords: Amino Acid Sequence
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
Schools: School of Applied Sciences
Depositing User: Hans Hennies
Date Deposited: 06 Jul 2016 15:48
Last Modified: 28 Aug 2021 12:05


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