Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer

Abstract

Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions. Two heterozygous missense mutations in the RHBDF2 gene were recently reported to be associated with TOC in three families: a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family. We aimed to validate these novel results in an independent material by screening RHBDF2 in a previously unreported Finnish TOC family. We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. Thus, we confirmed RHBDF2 mutations as the underlying cause of the TOC syndrome and our results suggest that the TOC associated mutations might be specific for this particular site in the RHBDF2 gene. These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families.

Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin

“…Two recent studies indicated that missense mutations in RHBDF2 (p.I186T, p.P189L, and p.D188N) underlie a familial tylosis with esophageal cancer syndrome in families in the United States, United Kingdom, Germany, and Finland (11,42). Based on our results on Rhbdf2 cub mutant mice, we predicted that increased AREG secretion due to dominant N-terminal mutations in RHBDF2 might drive these human pathological changes.…”

“…In the present study, we find that N-terminal-truncated iRhom2 promotes increased AREG production independent of ADAM17 activity, and thereby induces EGFR activation. In particular, the phenotype of Apc Min/+ Rhbdf2 +/cub mice recapitulates the increased susceptibility to epithelial cancers seen in patients with dominant RHBDF2 mutations (11,42). However, Rhbdf2 cub/cub mice did not spontaneously develop tumors, suggesting that the Rhbdf2 cub mutation might not drive cancer development but, instead, might promote tumor growth and progression by creating a conducive environment.…”

“…In humans, dominant mutations in the N terminus of the RHBDF2 gene are associated with hyperkeratosis and esophageal cancer (11,42). Although the mechanisms underlying the pathogenesis of hyperkeratosis and cancer are unclear, analyses of skin biopsies of patients suggest constitutive EGFR activation.…”

Dermatologic Manifestations of Cancer Syndromes

“…HowelYEvans syndrome (tylosis): autosomal dominant condition because of mutation in RHBDF2 gene, which plays a role in epithelial response to injury. The condition is characterized by thickening of the palmaplantar skin (hyperkeratosis) and is associated with increased risk for esophageal cancer (Saarinen et al, 2012). 11.…”

Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

“…TOC patients suffer from PPK, follicular papules, oral keratosis, and up to a 95% lifetime risk of developing oesophageal cancer (Ellis et al, 1994;Hennies et al, 1995;Stevens et al, 1996). TOC results from mutations in a specifi c region of the long N-terminus of the inactive rhomboid protein iRHOM2, encoded by the gene RHBDF2 (Blaydon et al, 2012;Saarinen et al, 2012). iRHOM2 (and its homologue iRHOM1) traffi c ADAM17 from the ER to the Golgi, where the inhibitory pro-domain is cleaved by furin (Adrain et al, 2012;McIlwain et al, 2012).…”