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Human Molecular Genetics Advance Access published online on March 1, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl042
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 22, 2005
Revised February 24, 2006
Accepted February 24, 2006

Article

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

Fiona E McRonald 1, Triantafillos Liloglou 2, George Xinarianos 2, Laura Hill 1, Lynn Rowbottom 1, Joanne E Langan 1, Anthony Ellis 3, Joan M Shaw 3, John K Field 4, and Janet M Risk 5 *

1 School of Dental Sciences, University of Liverpool, Liverpool, L69 3GN, UK
2 University of Liverpool Cancer Research Centre, Liverpool, L3 9TA UK
3 Dept. of Gastroenterology, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK
4 School of Dental Sciences, University of Liverpool, Liverpool, L69 3GN, UK; University of Liverpool Cancer Research Centre, Liverpool, L3 9TA UK
5 Molecular Genetics and Oncology Group, School of Dental Sciences, University of Liverpool, Edwards Building, Daulby Street, Liverpool, L69 3GN, UK

* To whom correspondence should be addressed.
Janet M Risk, E-mail: j.m.risk{at}liverpool.ac.uk


  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.


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