Human Molecular Genetics Advance Access originally published online on March 1, 2006
Human Molecular Genetics 2006 15(8):1271-1277; doi:10.1093/hmg/ddl042
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Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression
1Molecular Genetics and Oncology Group, School of Dental Sciences, University of Liverpool, Edwards Building, Daulby Street, Liverpool L69 3GN, UK, 2University of Liverpool Cancer Research Centre, Liverpool L3 9TA, UK and 3Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool L7 8XP, UK
* To whom correspondence should be addressed. Tel: +44 01517065265; Fax: +44 01517065809; Email: j.m.risk{at}liverpool.ac.uk
Received December 22, 2005; Revised February 17, 2006; Accepted February 24, 2006
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.
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