Novel microsatellite markers and single nucleotide polymorphisms refine the tylosis with oesophageal cancer (TOC) minimal region on 17q25 to 42.5 kb: sequencing does not identify the causative gene

Abstract

Tylosis (focal non-epidermolytic palmoplantar keratoderma) is associated with the early onset of squamous cell oesophageal cancer in three families. Linkage and haplotype analyses have previously mapped the tylosis with oesophageal cancer (TOC) locus to a 500kb region on chromosome 17q25 that is also implicated in sporadically occurring squamous cell oesophageal cancer. In the current study, 17 additional putative microsatellite markers were identified within this 500kb region using sequence data, and 7 of these were shown to be polymorphic in the UK and US families. In addition, our complete sequence analysis of the non-repetitive parts of the TOC minimal region has identified 53 novel and 6 known single nucleotide polymorphisms (SNPs) in one or both of these families. Further fine mapping of the TOC disease locus by haplotype analysis of the 7 polymorphic markers and 21 of the 59 SNPs has allowed the reduction of the minimal region to 42.5kb. One known and two putative genes are located within this region, but none of these genes show tylosis-specific mutations within their protein coding regions. Alternative mechanisms of disease gene action must therefore be considered.