Polymorphisms of the Carcinogen Detoxifying UDP-Glucuronosyltransferase UGT1A7 in Proximal Digestive Tract Cancer

Abstract

Cancer of the proximal digestive tract is associated with tobacco smoke and ethanol exposure. The UDP-glucuronosyltransferase (UGT) 1A7 is a detoxifying enzyme capable of tobacco-borne carcinogen detoxification and cellular protection and has been implicated as a cancer risk gene. In this study, UGT1A7 expression is demonstrated in oral, esophageal, and gastric tissue, which are the principle sites of proximal digestive tract cancer. Genomic DNA from the blood of 76 patients with esophageal, orolaryngeal and gastric cancer as well as from 210 healthy blood donors was analysed for the presence of UGT1A7 polymorphisms by sequencing and temperature gradient gel electrophoresis. Wild type UGT1A7 alleles were equally distributed between controls (19 %) and cancer patients (22 %). However, the UGT1A7*3 allele combining W208R, N129K and R131K missense mutations and exhibiting substantially reduced carcinogen detoxification activity was significantly associated with proximal gastrointestinal cancer and identified as a risk allele present in 32 % of cancer patients and 19 % of controls (P = 0.0008, OR 2,02 (95 %-CI 1.33-3.07)). We identify the significant association of the UGT1A7*3 allele encoding a low catalytic activity protein as a risk gene in proximal digestive tract cancer and as a potential marker for cancer susceptibility.

Zusammenfassung

Karzinome des proximalen Verdauungstraktes sind mit Tabakrauch- sowie Ethanolexposition assoziiert. Die UDP-Glukuronosyltransferase (UGT) 1A7 ist ein Metabolisierungsenzym, das Tabakrauchkarzinogene inaktivieren kann, zytoprotektiv wirkt und als Krebsrisiko-Gen identifiziert wurde. In dieser Studie wird UGT1A7-Expression in der Mukosa des Mundes, des Ösophagus und des Magens demonstriert, welche die Hauptlokalisationen proximaler Verdauungstraktkarzinome darstellen. Genomische DNA von 76 Patienten mit Ösophagus-, Oropharynx- und Magenkarzinomen sowie DNA von 210 gesunden Blutspendern wurden hinsichtlich der Frequenz von UGT1A7-Polymorphismen durch Sequenz- und Temperaturgradienten-Gelelektrophorese untersucht. Die Wildtyp-UGT1A7-Allele waren gleich zwischen Kontrollen (19 %) und Karzinompatienten (22 %) verteilt. Die Assoziation des UGT1A7*3-Allels, welches die W208R-, N129K- und R131K-Missense-Mutationen vereint mit proximalen Karzinomen des Gastrointestinaltraktes, war signifikant (32 % in Karzinompatienten, 19 % in Kontrollen, p = 0,0008, OR 2,02 (95 %-KI 1,33-3,07)). Diese Daten identifizieren UGT1A7*3 als Risiko-Allel für die proximale gastrointestinale Karzinogenese. Wir demonstrieren, dass UGT1A7*3, welches ein Protein mit niedriger katalytischer Entgiftungsaktivität kodiert, signifikant mit proximalen Karzinomen des Verdauungstraktes assoziiert ist und einen potenziellen Marker der Krebsdisposition darstellt.

Cancer Predisposition - Carcinogen Detoxification - Tissue-Specific Expression - UDP-Glucuronosyltransferase - Genetic Polymorphism

Krebs-Prädisposition - Karzinogen-Entgiftung - Gewebespezifische Expression - UDP-Glukuronosyltransferase - Genetischer Polymorphismus - Magenkarzinom - Ösophaguskarzinom

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