Environmental and genetic factors in bladder cancer: a multicentric case-control enquiry in Europe

Información del proyecto

Identificador del acuerdo de subvención: BMH4983243

Proyecto cerrado

Fecha de inicio 1 Abril 1998

Fecha de finalización 31 Diciembre 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

Ayuntamiento de Barcelona
Spain

Objetivo

Brief description: The only specific occupational exposures that have been unequivocally associated with excess bladder cancer risk are aromatic amines. Classical epidemiological approaches have not been able to identify other specific exposures accounting for the excess risks observed in many occupations. Evidence is controversial concerning environmental exposures such as water chlorination or environmental tobacco smoke. The role of many genetic polymorphisms for the occurrence of bladder cancer has not been well investigated, both concerning their modulating role on the effect of specific risk factors and also their role on the formation of aromatic amine - DNA adducts. In the last years, many studies have examined genetic alterations in bladder cancer such as mutations in the P53 gene. Their association with tobacco smoke, occupational exposure to aromatic amines and specific genetic polymorphisms is not well established.
A multicentric hospital based case-control study will be carried out in five EU countries (Denmark, France, Italy, Portugal and Spain) following parallel methods. Approximately 1,500 male and female incident bladder cancer cases and 1,500 noncancer hospital controls will be enrolled in the study during a period of two years. Subjects will be personally interviewed using a computer assisted structured questionnaire on sociodemographic characteristics, tobacco, occupation, environmental exposures, medical history, diet and other potential risk factors. Detailed supplementary information will be requested for specific occupations and industries. Blood, urine, normal urothelium and. fresh tumour samples and/or paraffin blocks (cases only) will be collected from the subjects. Specific centralised laboratory analyses will be carried out in Milan (aromatic amine-DNA adducts), Barcelona (p53 mutations), Paris, Lyon and Bethesda, US (genetic susceptibility). The core epidemiological database will be stored and analysed in Barcelona.

Keywords:
Urinary bladder; neoplasms; occupation; aromatic amines; genetic susceptibility; DNA adducts; p53 gene

In industrialised countries cancer of the bladder is the fifth most common cancer in men. In women it is about three times less frequent. In western populations cigarette smoking accounts for, at least, 50% of bladder cancers and occupational exposures around 20%. Aromatic amines (4-aminobiphenyl (4-ABP) and 4-chloro-o-toluidine(o-Tol)) are present in cigarette smoke. The highest levels are observed in black (air-cured) tobacco, which is possibly associated with a higher bladder cancer risk than blond tobacco. The only specific occupational exposures that have been unequivocally associated with excess bladder cancer risk are aromatic amines such as Bêta-naphthylamine, 4-ABP and o-Tol. Classical epidemiological approaches have not been able to identify other specific exposures accounting for the excess risks observed in many occupations. Evidence is controversial concerning other environmental exposures such as water chlorination, environmental tobacco smoke. Genetic polymorphisms, e.g. N-acetyl transferase 1 and 2 (NAT1, NAT2), glutathione transferase M1 (GSTM1) affecting carcinogen metabolising/detoxification enzymes may account for wide inter-individual variation in susceptibility to tobacco and occupational exposures for bladder cancer. The role of many of these polymorphisms for the occurrence of bladder cancer has been little or has not been investigated. The metabolites of aromatic amines are transported via the blood to the urinary bladder where they can bind to DNA. Only few, relatively small, studies have investigated the presence of 4-ABP adducts in connection with genetic polymorphisms while no studies have been reported on the in vivo formation of o-Tol DNA adducts. In the last years, many studies have examined genetic alterations in bladder cancer such as mutations in the P53 gene. Their association with tobacco smoke, occupational exposure to aromatic amines and specific geneticpolymorphisms is not well established.

A multicentric hospital based case-control study will be carried out in five EU countries following parallel methods. Approximately 1,400 male and female incident bladder cancer cases and 1,400 non-cancer hospital controls will be enrolled in the study during a period of two years. Subjects will be personally interviewed using a structured questionnaire, requesting detailed supplementary information for specific occupations and industries. Computer assisted interviews will be used in most centres. Blood, urine, normal urothelium and, fresh tumour samples and/or paraffin blocks (cases only) will be collected from the subjects.

The major specific objectives of the study are:
a) to evaluate the interaction of genetic and environmental exposures and particularly the modulating role of relevant genotypes (primarily NAT1, NAT2, GSTM1 and also GST Pi, DT-diaphorase, cathecol-o-methyltranferase, cytochrome P4501A2) on the effect of specific risk factors for bladder cancer;
b) to evaluate the risk of bladder cancer in relation to occupational exposures, exposure to different types of tobacco smoke and of environmental risk factors, particularly water chlorination, and environmental tobacco smoke, using state of the arl exposure assessment;
c) to quantify the exposure to environmental carcinogens measuring 4-ABP DNA adducts and o-To1 DNA adducts in bladde biopsies and evaluate the modulating role of relevant genotypes for the formation of these adducts;
d) to determine the frequency and spectrum of p53 mutations in tumour tissue and evaluate whether specific mutations (hotspots) are associated with specific exposures and also with the formation of 4-ABP o-Tol DNA adducts in bladder biopsies.

The lack of advancement in the identification of novel carcinogens associated with bladder cancer may be due to the fact that they only impact on selected individuals, perhaps through the interaction with specific genotypes. To test this hypothesis state-of-the-art epidemiologic techniques, state of the art laboratory techniques and a study population of sufficient size needs to bemused. In bladder cancer, no such studies have been conducted. We aim to examine both genetic and environmental factors and their interaction, and for this reason we have concentrated our efforts to a limited number of carefully selected hypotheses, studied in a large population sample.

Keywords: urinary bladder; neo plasms; occupation; environment; aromatic amines; genetic susceptibility; DNA adducts; p53 gene.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › medicina clínica › oncología › cáncer de vejiga
• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias médicas y de la salud › ciencias de la salud › nutrición
• ciencias naturales › ciencias químicas › química orgánica › aminas

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 4.5.2 - Interaction of genetic and occupational factors

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CON - Coordination of research actions

Coordinador

Ayuntamiento de Barcelona

• Aportación de la UE: Sin datos
• Dirección: 80,C/ Dr. Aiguader ; 08003 Barcelona ; España
• Coste total: Sin datos