Environmental factors and p53 mutation spectrum in lung cancer
Author: Bessö, Anna
Date: 2006-06-09
Location: Hillarpsalen, Retzius väg 8
Time: 9.00
Department: Institutet för miljömedicin (IMM) / Institute of Enviromental Medicine
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Thesis (521.9Kb)
Abstract
The use of molecular biomarkers, such as mutations in the p53 gene, has raised expectations for improving the resolution power in epidemiological studies. In this thesis we assessed the influence of smoking, environmental tobacco smoke (ETS), residential radon and arsenic on the p53 mutation prevalence and spectrum in lung tumors. Furthermore, we investigated the lung cancer risk among 316 cases and 727 controls in the area surrounding Rönnskärsverken, a non-ferrous metal smelter, and cases from this study were also included in the analyses of p53 mutations.
Tumor samples were collected from pathology departments and exons 5-8 of the p53 gene were analyzed using SSCP or DGGE screening in combination with DNA sequencing or using direct DNA sequencing for a total of 479 lung cancer cases, including 196 cases among never-smokers. Information on smoking, occupational and residential histories was collected through questionnaires and/or interviews of study subjects or next-of-kin. Exposure to residential radon was estimated based on measurements for a 32-year retrospective period in the dwellings of the study subjects.
An increased risk of lung cancer was indicated among men who had lived close to the nonferrous smelter, primarily among those exposed during the early years of operations, when emissions were high, and for less than 20 years, odds ratio (OR) 2.5, 95% confidence interval (CI) 0.9-7.1, compared to unexposed. In total, we detected 103 mutations in 99 lung tumors (mutation prevalence 21%). Tobacco smoking was associated with an increased p53 mutation prevalence (OR 2.4, 95% CI 1.1-5.1) and a higher proportion of G to T transversions whereas G to A transitions at CpG sites were more common among never-smokers. A higher p53 mutation prevalence was suggested also for exposure to residential radon, OR 2.8 (95% CI 0.8-9.3) for cases exposed to a time-weighted average level of more than 400 Bq /m3 compared to those exposed to less than 50 Bq /m3. Cases with exposure to both residential radon (>50 Bq /m3 ) and a long duration of ETS exposure (>3 0 years) showed a clear increase in prevalence of p53 mutations compared to unexposed (OR 4.9, 95% CI 1.2-21.1). For exposure to arsenic, a possible negative interaction with smoking was suggested (OR 0.5, 95% CI 0.2-1.2). Tumors from smokers without arsenic exposure had a greater variety of base-changes than tumors from smokers with arsenic exposure.
We could not detect any clear exposure specific spectra of p53 mutations in lung tumors associated with exposure to ETS, arsenic or residential radon. Weak associations may have been missed, however. Although mutations in the p53 gene did not seem to be a useful marker in our studies, our results provide a substantial addition to the available p53 data on never-smoking lung cancer cases and give new evidence on possible mechanistic pathways in environmentally induced lung cancer.
Tumor samples were collected from pathology departments and exons 5-8 of the p53 gene were analyzed using SSCP or DGGE screening in combination with DNA sequencing or using direct DNA sequencing for a total of 479 lung cancer cases, including 196 cases among never-smokers. Information on smoking, occupational and residential histories was collected through questionnaires and/or interviews of study subjects or next-of-kin. Exposure to residential radon was estimated based on measurements for a 32-year retrospective period in the dwellings of the study subjects.
An increased risk of lung cancer was indicated among men who had lived close to the nonferrous smelter, primarily among those exposed during the early years of operations, when emissions were high, and for less than 20 years, odds ratio (OR) 2.5, 95% confidence interval (CI) 0.9-7.1, compared to unexposed. In total, we detected 103 mutations in 99 lung tumors (mutation prevalence 21%). Tobacco smoking was associated with an increased p53 mutation prevalence (OR 2.4, 95% CI 1.1-5.1) and a higher proportion of G to T transversions whereas G to A transitions at CpG sites were more common among never-smokers. A higher p53 mutation prevalence was suggested also for exposure to residential radon, OR 2.8 (95% CI 0.8-9.3) for cases exposed to a time-weighted average level of more than 400 Bq /m3 compared to those exposed to less than 50 Bq /m3. Cases with exposure to both residential radon (>50 Bq /m3 ) and a long duration of ETS exposure (>3 0 years) showed a clear increase in prevalence of p53 mutations compared to unexposed (OR 4.9, 95% CI 1.2-21.1). For exposure to arsenic, a possible negative interaction with smoking was suggested (OR 0.5, 95% CI 0.2-1.2). Tumors from smokers without arsenic exposure had a greater variety of base-changes than tumors from smokers with arsenic exposure.
We could not detect any clear exposure specific spectra of p53 mutations in lung tumors associated with exposure to ETS, arsenic or residential radon. Weak associations may have been missed, however. Although mutations in the p53 gene did not seem to be a useful marker in our studies, our results provide a substantial addition to the available p53 data on never-smoking lung cancer cases and give new evidence on possible mechanistic pathways in environmentally induced lung cancer.
List of papers:
I. Yngveson A, Williams C, Hjerpe A, Lundeberg J, Soderkvist P, Pershagen G (1999). p53 Mutations in lung cancer associated with residential radon exposure. Cancer Epidemiol Biomarkers Prev. 8(5): 433-8.
Pubmed
II. Besso A, Nyberg F, Pershagen G (2003). Air pollution and lung cancer mortality in the vicinity of a nonferrous metal smelter in Sweden. Int J Cancer. 107(3): 448-52.
Pubmed
III. Besso A, Ahlberg S, Carling U, Hjerpe A, Ingelman-Sundberg M, Nyberg F, Pershagen G (2006). p53 mutations in lung cancer cases exposed to arsenic at a non-ferrous metal smelter. [Submitted]
IV. Besso A, Hjerpe A, Husgafvel-Pursiainen K, Pershagen G, Soderkvist P, Nyberg F (2006). TP53 gene mutations in lung cancer cases exposed to ETS and residential radon. [Submitted]
I. Yngveson A, Williams C, Hjerpe A, Lundeberg J, Soderkvist P, Pershagen G (1999). p53 Mutations in lung cancer associated with residential radon exposure. Cancer Epidemiol Biomarkers Prev. 8(5): 433-8.
Pubmed
II. Besso A, Nyberg F, Pershagen G (2003). Air pollution and lung cancer mortality in the vicinity of a nonferrous metal smelter in Sweden. Int J Cancer. 107(3): 448-52.
Pubmed
III. Besso A, Ahlberg S, Carling U, Hjerpe A, Ingelman-Sundberg M, Nyberg F, Pershagen G (2006). p53 mutations in lung cancer cases exposed to arsenic at a non-ferrous metal smelter. [Submitted]
IV. Besso A, Hjerpe A, Husgafvel-Pursiainen K, Pershagen G, Soderkvist P, Nyberg F (2006). TP53 gene mutations in lung cancer cases exposed to ETS and residential radon. [Submitted]
Issue date: 2006-05-19
Rights:
Publication year: 2006
ISBN: 91-7140-675-1
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