title: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
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.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Blaydon
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Etheridge
authors.forename: Janet M
authors.initials: JM
authors.lastname: Risk
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Hennies
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gay
authors.forename: Rebecca
authors.initials: R
authors.lastname: Carroll
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McRonald
authors.forename: Howard P
authors.initials: HP
authors.lastname: Stevens
authors.forename: Nigel K
authors.initials: NK
authors.lastname: Spurr
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Anthony
authors.initials: A
authors.lastname: Ellis
authors.forename: Janusz
authors.initials: J
authors.lastname: Jankowski
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
mesh_terms: D000595:Amino Acid Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005091:Exons; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D015776:Keratoderma, Palmoplantar, Diffuse / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D012697:Serine Endopeptidases; D057057:Serine Proteases / Q000235:genetics*; D020506:Untranslated Regions
chemical_list: D020506:Untranslated Regions; C512478:EGFR protein, human; D066246:ErbB Receptors; D057057:Serine Proteases; D012697:Serine Endopeptidases; C545655:RHBDL2 protein, human