title: Down-regulation 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 (SCOC) in three families. Our previous linkage and haplotype analyses have mapped the tylosis with oesophageal cancer (TOC) locus to a 42.5 kb region on chromosome 17q25 that has also been implicated in the aetiology of sporadically occurring SCOC from a number of different geographical populations. Oesophageal cancer is one of the 10 leading causes of cancer mortality worldwide. No inherited disease-causing mutations have been identified in the genes located in the 42.5 kb 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.
authors.affiliation: Molecular Genetics and Oncology Group, School of Dental Sciences, University of Liverpool, Edwards Building, Daulby Street, Liverpool L69 3GN, UK.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McRonald
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
authors.forename: George
authors.initials: G
authors.lastname: Xinarianos
authors.forename: Laura
authors.initials: L
authors.lastname: Hill
authors.forename: Lynn
authors.initials: L
authors.lastname: Rowbottom
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Langan
authors.forename: Anthony
authors.initials: A
authors.lastname: Ellis
authors.forename: Joan M
authors.initials: JM
authors.lastname: Shaw
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Janet M
authors.initials: JM
authors.lastname: Risk
mesh_terms: D022981:Allelic Imbalance; D045744:Cell Line, Tumor; D002886:Chromosomes, Human, Pair 17; D000078842:Cytoglobin; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015776:Keratoderma, Palmoplantar, Diffuse / Q000235:genetics* / Q000378:metabolism; D008297:Male; D017422:Sequence Analysis, DNA
chemical_list: C000627265:CYGB protein, human; D000078842:Cytoglobin; D005914:Globins