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.
Key words
Cancer Predisposition - Carcinogen
Detoxification - Tissue-Specific
Expression - UDP-Glucuronosyltransferase - Genetic
Polymorphism
Schlüsselwörter
Krebs-Prädisposition - Karzinogen-Entgiftung - Gewebespezifische
Expression - UDP-Glukuronosyltransferase - Genetischer
Polymorphismus - Magenkarzinom - Ösophaguskarzinom
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Christian P. Strassburg, PD Dr.
Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover
Medical School
Carl-Neuberg-Straße 1
30625 Hannover
Germany
Email: strassburg.christian@mh-hannover.de