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 500-kb region on chromosome 17q25 that has also been implicated in sporadically occurring squamous cell oesophageal cancer. In the current study, 17 additional putative microsatellite markers were identified within this 500-kb region by using sequence data and seven 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 identified 53 novel and six 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 seven polymorphic markers and 21 of the 59 SNPs allowed the reduction of the minimal region to 42.5 kb. One known and two putative genes are located within this region but none of these genes shows tylosis-specific mutations within their protein-coding regions. Alternative mechanisms of disease gene action must therefore be considered.
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References
Brevern M von, Hollstein MC, Risk JM, Garde J, Bennett WP, Harris CC, Muehlbauer KR, Field JK (1998) Loss of heterozygosity in sporadic oesophageal tumours in the tylosis oesophageal cancer (TOC) gene region of chromosome 17. Oncogene 17:2101–2105
Ellis A, Field JK, Field AE, Friedmann PS, Fryer A, Howard P, Leigh IM, Risk JM, Shaw JM, Whittaker J (1994) Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family—a review of six generations. Eur J Cancer Oral Oncol 30B:102–112
Gibbs RA, Cockerill M (1995) Working on the assembly line. Trends Biochem Sci 20:162–163
Gottlieb M, Chavko M (1987) Silver staining of native and denatured eucaryotic DNA in agarose gels. Anal Biochem 165:33–37
Hennies HC, Hagedorn M, Reis A (1995) Palmoplantar keratoderma in association with carcinoma of the esophagus maps to chromosome 17q distal to the keratin gene cluster. Genomics 29:537–540
Howel-Evans W, McConnell RB, Clarke CA, Sheppard PM (1958) Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis): a study of two families. Q J Med 27:413–429
International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921
Iwaya T, Maesawa C, Ogasawara S, Tamura G (1998) Tylosis esophageal cancer locus on chromosome 17q25.1 is commonly deleted in sporadic human esophageal cancer. Gastroenterology 114:1206–1210
Kalikin LM, George RAV, Keller MP, Bort S, Bowler NS, Law DJ, Chance PF, Petty EM (1999) An integrated physical and gene map of human distal chromosome 17q24-proximal 17q25 encompassing multiple disease loci. Genomics 57:36–42
Kelsell DP, Risk JM, Leigh IM, Stevens HP, Ellis A, Hennies HC, Reis A, Weissenbach J, Bishop DT, Spurr NK, Field JK (1996) Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC). Hum Mol Genet 5:857–860
Kuhlenbaumer G, Schirmacher A, Meuleman J, Tissir F, Del-Favero J, Stogbauer F, Young P, Ringelstein B, Van Broeckhoven C, Timmerman V (1999) A sequence-ready BAC/PAC contig and partial transcript map of approximately 1.5 Mb in human chromosome 17q25 comprising multiple disease genes. Genomics 62:242–250
Langan JE, Rowbottom L, Liloglou T, Field JK, Risk JM (2002) Sequencing of difficult templates containing poly(A/T) tracts: closure of sequence gaps. Biotechniques 33:276–280
Risk JM, Field EA, Whittaker J, Fryer A, Ellis A, Shaw JM, Friedmann PS, Bishop DT, Bodmer J, Leigh IM, Field JK (1994) Tylosis oesophageal cancer mapped. Nat Genet 8:319–321
Risk JM, Ruhrberg C, Hennies HC, Mills HS, Di Colandrea T, Evans KE, Ellis A, Watt FM, Bishop DT, Spurr NK, Stevens HP, Leigh IM, Reis A, Kelsell DP, Field JK (1999) Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): the integration of genetic and physical maps of the TOC region on 17q25. Genomics 59:234–242
Risk JM, Evans KE, Jones J, Langan JE, Rowbottom L, McRonald FE, Mills HS, Ellis A, Shaw JM, Leigh IM, Kelsell DP, Field JK (2002) Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial tylosis oesophageal cancer (TOC) locus. Oncogene 21:6395–6402
Scherf M, Klingenhoff A, Werner T (2000) Highly specific localization of promoter regions in large genomic sequences by PromoterInspector: a novel context analysis approach. J Mol Biol 297:599–606
Stevens HP, Kelsell DP, Bryant SP, Bishop DT, Spurr NK, Weissenbach J, Marger D, Marger RS, Leigh IM (1996) Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch Dermatol 132:640–651
Acknowledgements
This work was supported by grants from the Cancer Research UK and the North West Cancer Research Fund. Sequencing performed at the Wellcome Trust Sanger Institute was funded by the Wellcome Trust.
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Langan, J.E., Cole, C.G., Huckle, E.J. et al. 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. Hum Genet 114, 534–540 (2004). https://doi.org/10.1007/s00439-004-1100-3
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DOI: https://doi.org/10.1007/s00439-004-1100-3