Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0546837 (esophageal cancer)
 8,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.
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PMID:RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. 2226 16

Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions. Two heterozygous missense mutations in the RHBDF2 gene were recently reported to be associated with TOC in three families: a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family. We aimed to validate these novel results in an independent material by screening RHBDF2 in a previously unreported Finnish TOC family. We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. Thus, we confirmed RHBDF2 mutations as the underlying cause of the TOC syndrome and our results suggest that the TOC associated mutations might be specific for this particular site in the RHBDF2 gene. These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families.
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PMID:Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. 2263 70

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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PMID:Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms. 2641 62

Esophageal cancer is common worldwide, and often fatal. The major histological subtype is esophageal squamous cell carcinoma (ESCC). ESCC shows familial aggregation and high heritability. Mutations in RHBDF2 cause tylosis, a very rare disorder characterized by high life-time risk of ESCC, but no other well-established predisposition genes have been identified. To identify candidate susceptibility variants for ESCC we utilized the Population Information System and the Finnish cancer registry to find study materials by clustering ESCC patients by family name at birth and municipality at birth. We collected archival tissue material and exome sequenced a total of 30 ESCC cases. We prioritized shared, deleterious and rare variants that were significantly enriched in our sample set compared to Finnish and population subset specific controls. Six variants passed filtering, the most frequent being a nonsense mutation in DNAH9 (p.Tyr1573Ter) found in four unrelated patients. DNAH9 has been reported to be frequently lost in ESCC tumors. In this study, one patient's tumor showed loss of the wild type allele of DNAH9 suggesting a tumor suppressive function. A missense variant in GKAP1 was shared by three patients, and missense variants in BAG1, NFX1, FUK, and DDOST by two each. EP300 which has previously been implicated in the genesis of ESCC had a missense variant segregating in three affected individuals in a single family. If validated in independent patient sets, these variants could serve as a tool towards prevention and early diagnosis of ESCC.
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PMID:Candidate susceptibility variants for esophageal squamous cell carcinoma. 2816 52

Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling. Furthermore, we and other investigators have used these models to generate new insights into the causes and progression of TOC, including findings suggesting a tissue-specific role of the RHBDF2-EGFR pathway, rather than a role of the immune system, in mediating TOC; and indicating that amphiregulin, an EGFR ligand, is a functional driver of the disease. This review highlights the mouse models of TOC available to researchers for use in investigating the disease mechanisms and possible therapies, and the significance of genetic modifiers of the disease identified in these models in delineating the underlying molecular mechanisms.
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PMID:RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models? 3002 99