MedWire News: UK researchers have pinpointed a single genetic defect that underlies "tylosis with [o]esophageal cancer [TOC]," an inherited syndrome that confers a high risk for esophageal cancer.
Writing in the American Journal of Human Genetics, David Kelsell (Queen Mary University of London) and colleagues say that TOC is caused by a faulty version of the RHBDF2 gene, which encodes the inactive rhomboid protease RHBDF2 (iRhom2). TOC is an autosomal dominant syndrome that has been studied in three extensive pedigrees from the UK, USA, and Germany, explain Kelsell and co-authors in background information.
The syndrome is characterized by palmoplantar keratoderma, oral leukokeratosis, follicular hyperkeratosis, and a high lifetime risk for esophageal cancer. The cutaneous phenotype is fully penetrant by the time of puberty, and the incidence of other cancers in these families is not altered.
In earlier work, Kelsell's team mapped the TOC locus to a small region on chromosome 17q25. In the current study, the team drew on technologic advances, including the development of high-throughput sequencing platforms, to revisit the TOC locus.
They obtained DNA from an affected individual in the UK and analyzed it using a targeted capture array. This identified two missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu]) in the RHBDF2 gene.
Next, the team measured levels of RHBDF2 protein in skin samples taken from people with tylosis. They found that the distribution of RHBDF2 was altered in tylotic skin compared with normal skin.
Furthermore, they showed that tylotic keratinocytes exhibit decreased levels of epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to both normal cells and normal cells stimulated with exogenous epidermal growth factor.
"It would thus appear that EGFR signalling is dysregulated in the tylotic cells," remark Kelsell et al.
Finally, they found that RHBDF2 distribution was altered in a similar manner in samples from people with tylosis and from people with sporadic squamous esophageal tumors.
This suggests that RHBDF2 mutations play a role in the etiology of non-TOC-related esophageal cancer, say the authors.
Commenting on their findings in a press statement, Kelsell said: "In studying this relatively rare condition, we have made an important discovery about a cancer that is all too common.
"By analyzing the complex biology which causes a particular type of cancer we begin to understand which treatments might be effective and also which treatments are unlikely to help."
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