Downregulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression

Abstract

Tylosis (focal non-epidermolytic palmoplantar keratoderma) is an autosomal dominant skin disorder that is associated with the early onset of squamous cell oesophageal cancer in three families. Our previous linkage and haplotype analyses have mapped the tylosis with oesophageal cancer (TOC) locus to a 42.5kb region on chromosome 17q25 that has also been implicated in the aetiology of sporadically occurring squamous cell oesophageal cancer from a number of different geographical populations. Oesophageal cancer is one of the ten leading causes of cancer mortality worldwide. No inherited disease-causing mutations have been identified in the genes located in the 42.5kb minimal region. We now show that cytoglobin gene expression in oesophageal biopsies from tylotic patients is dramatically reduced by approximately 70% compared with normal oesophagus. Furthermore, both alleles are equally repressed. Given the autosomal dominant nature of the disease, these results exclude haploinsufficiency as a mechanism of the disease and instead suggest a novel trans-allele interaction. We also show that the promoter is hypermethylated in sporadic oesophageal cancer samples: this may constitute the ‘second hit’ of a gene previously implicated in this disease by allelic imbalance studies.