The Experts below are selected from a list of 243 Experts worldwide ranked by ideXlab platform
Anthony Ellis - One of the best experts on this subject based on the ideXlab platform.
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Tylosis with oesophageal cancer diagnosis management and molecular mechanisms
Orphanet Journal of Rare Diseases, 2015Co-Authors: Anthony Ellis, Janet M. Risk, T Maruthappu, David P. KelsellAbstract:Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95 % at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2–5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with Tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of Tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of Tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients.
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defining the endoscopic appearances of Tylosis using conventional and narrow band imaging a case series
Endoscopy, 2011Co-Authors: Howard Smart, Sreedhar Subramanian, S Khalid, Fiona Campbell, Anthony EllisAbstract:Tylosis is an autosomal dominant skin disorder strongly associated with esophageal squamous cell cancer. We present a single-operator experience of utilizing conventional endoscopy and narrow-band imaging with magnification to characterize esophageal appearances in Tylosis. Nineteen consecutive patients with Tylosis attending for surveillance endoscopy were studied. White-light imaging (WLI) and narrow-band imaging (NBI) were undertaken, with magnification being performed as necessary. On WLI, we classified 12 patients as having mild change, 5 moderate change, and 2 severe change. WLI can define changes to the esophageal mucosa of variable hyperkeratosis and identify more significant focal abnormalities. NBI enhances these mucosal changes, and NBI with magnification can demonstrate intrapapillary capillary loop changes compatible with dysplasia, prompting consideration of surgery. This report is the first to characterize the endoscopic appearances in Tylosis.
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down regulation of the cytoglobin gene located on 17q25 in Tylosis with oesophageal cancer toc evidence for trans allele repression
Human Molecular Genetics, 2006Co-Authors: Fiona E. Mcronald, Anthony Ellis, Joanne E. Langan, Lynn Rowbottom, Joan M. Shaw, John K Field, Triantafillos Liloglou, George Xinarianos, Laura Hill, Janet M. RiskAbstract: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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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
Human Genetics, 2004Co-Authors: Joanne E. Langan, Anthony Ellis, Charlotte G. Cole, Elisabeth J. Huckle, Shaun Byrne, Fiona E. Mcronald, Lynn Rowbottom, Joan M. Shaw, Irene M. Leigh, David P. KelsellAbstract: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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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, 1999Co-Authors: Janet M. Risk, Anthony Ellis, Christiana Ruhrberg, Hans Christian Hennies, H. S. Mills, T. Di Colandrea, K. E. Evans, Fiona M. Watt, D.t. Bishop, Nigel K. SpurrAbstract:Focal nonepidermolytic palmoplantar keratoderma (NEPPK), or Tylosis, is an autosomal, dominantly inherited disorder of the skin that manifests as focal thickening of the palmar and plantar surfaces. In three families studied, the skin disorder cosegregates with esophageal cancer and oral lesions. New haplotype analysis, presented here, places the Tylosis esophageal cancer (TOC) locus between D17S1839 and D17S785. Envoplakin (EVPL) is a protein component of desmosomes and the cornified envelope that is expressed in epidermal and esophageal keratinocytes and has been localized to the TOC region. Mutation analysis of EVPL in the three affected families failed to show Tylosis-specific mutations, and haplotype analysis of three intragenic sequence polymorphisms of the EVPL gene placed it proximal to D17S1839. Confirmation of the exclusion of EVPL as the TOC gene by location was obtained by integration of the genetic and physical mapping data using radiation hybrid, YAC, BAC, and PAC clones. This new physical map will allow further identification of candidate genes underlying NEPPK associated with esophageal cancer, which may also be implicated in the development of sporadic squamous cell esophageal carcinoma and Barrett's adenocarcinoma.
Janet M. Risk - One of the best experts on this subject based on the ideXlab platform.
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Tylosis with oesophageal cancer diagnosis management and molecular mechanisms
Orphanet Journal of Rare Diseases, 2015Co-Authors: Anthony Ellis, Janet M. Risk, T Maruthappu, David P. KelsellAbstract:Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95 % at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2–5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with Tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of Tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of Tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients.
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down regulation of the cytoglobin gene located on 17q25 in Tylosis with oesophageal cancer toc evidence for trans allele repression
Human Molecular Genetics, 2006Co-Authors: Fiona E. Mcronald, Anthony Ellis, Joanne E. Langan, Lynn Rowbottom, Joan M. Shaw, John K Field, Triantafillos Liloglou, George Xinarianos, Laura Hill, Janet M. RiskAbstract: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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the Tylosis esophageal cancer toc locus more than just a familial cancer gene
Diseases of The Esophagus, 1999Co-Authors: Janet M. Risk, J Garde, H. S. Mills, K. E. Evans, Julie R Dunn, M Hollstein, John K FieldAbstract:Tylosis (focal non-epidermolytic palmoplantar keratoderma; NEPPK) is associated with esophageal cancer in three families, two of which contain six or seven generations. The causative locus, the Tylosis esophageal cancer (TOC) gene, has been localized to a small region on chromosome 17q25. Recent loss of heterozygosity (LOH) studies have indicated a role for the TOC gene in sporadic squamous cell esophageal cancer and Barrett’s adenocarcinoma. We have now integrated genetic and physical mapping data from the TOC region, based on microsatellite markers and radiation hybrid, yeast (YAC), bacterial (BAC) and P1 artificial chromosomal (PAC) clones, and formed a partial minimal contig of one non-chimeric YAC (330 kb) and one PAC. Twenty-three candidate genes, including envoplakin (EVPL), were mapped against this contig, but only one was shown to be located within the minimal region. This physical map will allow further characterization of the region and identification of a gene implicated in both familial and sporadic squamous cell esophageal carcinoma and Barrett’s adenocarcinoma.
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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, 1999Co-Authors: Janet M. Risk, Anthony Ellis, Christiana Ruhrberg, Hans Christian Hennies, H. S. Mills, T. Di Colandrea, K. E. Evans, Fiona M. Watt, D.t. Bishop, Nigel K. SpurrAbstract:Focal nonepidermolytic palmoplantar keratoderma (NEPPK), or Tylosis, is an autosomal, dominantly inherited disorder of the skin that manifests as focal thickening of the palmar and plantar surfaces. In three families studied, the skin disorder cosegregates with esophageal cancer and oral lesions. New haplotype analysis, presented here, places the Tylosis esophageal cancer (TOC) locus between D17S1839 and D17S785. Envoplakin (EVPL) is a protein component of desmosomes and the cornified envelope that is expressed in epidermal and esophageal keratinocytes and has been localized to the TOC region. Mutation analysis of EVPL in the three affected families failed to show Tylosis-specific mutations, and haplotype analysis of three intragenic sequence polymorphisms of the EVPL gene placed it proximal to D17S1839. Confirmation of the exclusion of EVPL as the TOC gene by location was obtained by integration of the genetic and physical mapping data using radiation hybrid, YAC, BAC, and PAC clones. This new physical map will allow further identification of candidate genes underlying NEPPK associated with esophageal cancer, which may also be implicated in the development of sporadic squamous cell esophageal carcinoma and Barrett's adenocarcinoma.
David P. Kelsell - One of the best experts on this subject based on the ideXlab platform.
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Tylosis with oesophageal cancer diagnosis management and molecular mechanisms
Orphanet Journal of Rare Diseases, 2015Co-Authors: Anthony Ellis, Janet M. Risk, T Maruthappu, David P. KelsellAbstract:Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95 % at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2–5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with Tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of Tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of Tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients.
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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
Human Genetics, 2004Co-Authors: Joanne E. Langan, Anthony Ellis, Charlotte G. Cole, Elisabeth J. Huckle, Shaun Byrne, Fiona E. Mcronald, Lynn Rowbottom, Joan M. Shaw, Irene M. Leigh, David P. KelsellAbstract: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.
John K Field - One of the best experts on this subject based on the ideXlab platform.
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down regulation of the cytoglobin gene located on 17q25 in Tylosis with oesophageal cancer toc evidence for trans allele repression
Human Molecular Genetics, 2006Co-Authors: Fiona E. Mcronald, Anthony Ellis, Joanne E. Langan, Lynn Rowbottom, Joan M. Shaw, John K Field, Triantafillos Liloglou, George Xinarianos, Laura Hill, Janet M. RiskAbstract: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.
-
the Tylosis esophageal cancer toc locus more than just a familial cancer gene
Diseases of The Esophagus, 1999Co-Authors: Janet M. Risk, J Garde, H. S. Mills, K. E. Evans, Julie R Dunn, M Hollstein, John K FieldAbstract:Tylosis (focal non-epidermolytic palmoplantar keratoderma; NEPPK) is associated with esophageal cancer in three families, two of which contain six or seven generations. The causative locus, the Tylosis esophageal cancer (TOC) gene, has been localized to a small region on chromosome 17q25. Recent loss of heterozygosity (LOH) studies have indicated a role for the TOC gene in sporadic squamous cell esophageal cancer and Barrett’s adenocarcinoma. We have now integrated genetic and physical mapping data from the TOC region, based on microsatellite markers and radiation hybrid, yeast (YAC), bacterial (BAC) and P1 artificial chromosomal (PAC) clones, and formed a partial minimal contig of one non-chimeric YAC (330 kb) and one PAC. Twenty-three candidate genes, including envoplakin (EVPL), were mapped against this contig, but only one was shown to be located within the minimal region. This physical map will allow further characterization of the region and identification of a gene implicated in both familial and sporadic squamous cell esophageal carcinoma and Barrett’s adenocarcinoma.
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oral Tylosis a re appraisal
Oral Oncology, 1997Co-Authors: E A Field, Anthony Ellis, P S Friedmann, I M Leigh, John K FieldAbstract:The oral lesions in patients with Tylosis (palmoplantar keratoderma) associated with oesophageal cancer, are evaluated, based on their clinical presentation, histological features and long term follow-up. The terminology of these lesions is discussed, together with a proposed reclassification of some forms of palmoplantar keratoderma.
Fiona E. Mcronald - One of the best experts on this subject based on the ideXlab platform.
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down regulation of the cytoglobin gene located on 17q25 in Tylosis with oesophageal cancer toc evidence for trans allele repression
Human Molecular Genetics, 2006Co-Authors: Fiona E. Mcronald, Anthony Ellis, Joanne E. Langan, Lynn Rowbottom, Joan M. Shaw, John K Field, Triantafillos Liloglou, George Xinarianos, Laura Hill, Janet M. RiskAbstract: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.
-
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
Human Genetics, 2004Co-Authors: Joanne E. Langan, Anthony Ellis, Charlotte G. Cole, Elisabeth J. Huckle, Shaun Byrne, Fiona E. Mcronald, Lynn Rowbottom, Joan M. Shaw, Irene M. Leigh, David P. KelsellAbstract: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.
