Abstract
Tylosis with esophageal cancer（TOC）/Howel-Evans syndrome is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesion, and high-risk group of esophageal cancer. Previous studies localized the TOC locus to a small genomic region of 17q25.1–q25.2. Using a targeted capture array and next-generation sequencing, two kinds of missense mutations of RHBDF2 gene were detected in genomic DNA from patients with TOC. RHBDF2 is a family of seven transmembrane–spanning protein called rhomboids, but has been not yet known its function. It is thought that RHBDF2 regulate protease activity and EGF signaling by targeting ligands of EGFR. The study of Baydon DC et al suggested that the altered RHBDF2 protein, which was derived from the mutant alleles, had a property of gain-of-function, because of sustaining of EGFR signaling. It is assumed that this sustained EGFR signaling leads to hyperproliferative state. Moreover, Baydon DC et al proposed a hypothesis that tylosis results from dysregulated wound repair that lead to precancerous lesions in the esophagus and nonkeratinized epithelium of the upper gastrointestinal tract. Because similar biochemical characteristics were observed in not only TOC but also sporadic esophageal cancer, it is concerned some esophageal cancers might be resistant to treatment with EGFR-inhibitors. Therefore, developing therapies targeted to RHBDF2-regulated pathways could be more effective against esophageal cancers.
