Environment and Breast Cancer: Science Review
About
Associations between polycyclic aromatic hydrocarbon-related exposures and p53 mutations in breast tumors
Mordukhovich, I., Rossner, P., Jr., Terry, M. B., Santella, R., Zhang, Y. J., Hibshoosh, H., Memeo, L., Mansukhani, M., Long, C. M., Garbowski, G., Agrawal, M., Gaudet, M. M., Steck, S. E., Sagiv, S. K., Eng, S. M., Teitelbaum, S. L., Neugut, A. I., Conway-Dorsey, K., Gammon, M. D. Environ Health Perspect. 2010. 118:4, 511-8.
Topic area
Environmental pollutant - PAHs
Environmental pollutant - PAHs
Study design
Population based case-control
Population based case-control
Funding agency
NCI NIEHS U.S. Army Breast Cancer Research Foundat
NCI NIEHS U.S. Army Breast Cancer Research Foundat
Study Participants
Number of Cases
487
487
Menopausal Status
The menopausal status of women included in this study is listed here.
No analysis based on menopausal status
Number of Controls
Controls: 941
Controls: 941
Participant selection: Inclusion and exclusion criteria
Criteria used to select participants in the study.
Female residents of Nassau and Suffolk Counties (Long Island), NY, participating in the Long Island Breast Cancer Study Project, age 20 or older, English-speaking, newly diagnosed with in situ or invasive breast cancer in 1996-1997. Cases identified by regional hospital pathology laboratories. Controls had no breast cancer history and were matched by 5-year age group, identified by random-digit-dialing or Medicare records (for women 65 and older). Approximately 1102 cases (73.1% of LIBCSP cases) and 1140 controls (73.3% of LIBCSP controls) provided a blood sample; the analyses reported here were limited to women for whom PAH-DNA adducts were assessed in blood samples and for whom samples could be sufficiently genotyped, which is reflected in the number of cases/controls reported above. The main reason that samples could not be genotyped (<10%) was insufficient DNA.
Comment about participation selection
In the LIBCSP, giving a blood sample was positively associated with being white, ever using alcohol, ever using HRT, ever having a mammography, and lactation history. Older women and former smokers were less likely to give blood. Blood donation was not associated with case-control status, so these differences between the total study population and the sub-population who donated blood should not bias the findings, but could affect generalizability. Tumor tissue for p53 analysis was obtained from 67% of cases. The analyses reported here were also limited to women for whom PAH-DNA adducts were assessed in blood samples, which is reflected in the number of cases/controls reported above.
In the LIBCSP, giving a blood sample was positively associated with being white, ever using alcohol, ever using HRT, ever having a mammography, and lactation history. Older women and former smokers were less likely to give blood. Blood donation was not associated with case-control status, so these differences between the total study population and the sub-population who donated blood should not bias the findings, but could affect generalizability. Tumor tissue for p53 analysis was obtained from 67% of cases. The analyses reported here were also limited to women for whom PAH-DNA adducts were assessed in blood samples, which is reflected in the number of cases/controls reported above.
Exposure Investigated
Exposures investigated
PAH-DNA adducts were measured by competitive enzyme linked immunosorbent assay (ELISA) in blood samples obtained near time of diagnosis/reference. Samples with <15% inhibition were considered non-detect. Lifetime intake of grilled and smoked meat, active
PAH-DNA adducts were measured by competitive enzyme linked immunosorbent assay (ELISA) in blood samples obtained near time of diagnosis/reference. Samples with <15% inhibition were considered non-detect. Lifetime intake of grilled and smoked meat, active
How exposure was measured
Biological Questionnaire, in person
Biological Questionnaire, in person
Exposure assessment comment
Recall bias is a concern for self-reported lifetime diet and smoking history, although this would not affect case-case comparisons. PAH-DNA adducts reflect recent exposure. Blood obtained after diagnosis may not capture the relevant etiologic period. The relationship of PAH-DNA adducts to specific exposure sources is poorly understood, so this measure may not correctly rank the exposures relevant to disease.
Recall bias is a concern for self-reported lifetime diet and smoking history, although this would not affect case-case comparisons. PAH-DNA adducts reflect recent exposure. Blood obtained after diagnosis may not capture the relevant etiologic period. The relationship of PAH-DNA adducts to specific exposure sources is poorly understood, so this measure may not correctly rank the exposures relevant to disease.
Confounders considered
Other breast cancer risk factors, such as family history, age at first birth, and hormone replacement therapy use, that were taken into account in the study.
Based on causal diagram: Age at menarche, income, smoking status, grilled/smoked meat, race, energy intake, alcohol use, education, and age at diagnosis
Genetic characterization included
If the study analyzed relationships between environmental factors and inherited genetic variations, this field will be marked “Yes.” “No”, if not.
Yes
Strength of associations reported
Compared to those with non-detectable PAH-DNA adducts:
p53 mutation, detectable PAH-DNA adducts: aOR 1.28 (95% CI 0.71-2.31)
no p53 mutation, detectable PAH-DNA adducts: aOR 1.33 (95% CI 1.02-1.73)
G:C to A:T transitions at CpG sites, detectable PAH-DNA adducts: aOR 1.53 (95% CI 0.55-4.23)
G:C to A:T transitions at non-CpG sites, detectable PAH-DNA adducts: aOR 1.09 (95% CI 0.41-2.85)
Insertions/deletions, detectable PAH-DNA adducts: aOR 4.77 (95% CI 0.63-36.25)
Missense mutations, detectable PAH-DNA adducts: aOR 0.67 (95% CI 0.33-1.36)
Nonsense mutations, detectable PAH-DNA adducts: aOR 2.60 (95% CI 0.31-21.94)
Frameshift mutations, detectable PAH-DNA adducts: aOR 4.85 (95% CI 0.62-37.75)
Compared to those with non-detectable PAH-DNA adducts:
p53 mutation, detectable PAH-DNA adducts: aOR 1.28 (95% CI 0.71-2.31)
no p53 mutation, detectable PAH-DNA adducts: aOR 1.33 (95% CI 1.02-1.73)
G:C to A:T transitions at CpG sites, detectable PAH-DNA adducts: aOR 1.53 (95% CI 0.55-4.23)
G:C to A:T transitions at non-CpG sites, detectable PAH-DNA adducts: aOR 1.09 (95% CI 0.41-2.85)
Insertions/deletions, detectable PAH-DNA adducts: aOR 4.77 (95% CI 0.63-36.25)
Missense mutations, detectable PAH-DNA adducts: aOR 0.67 (95% CI 0.33-1.36)
Nonsense mutations, detectable PAH-DNA adducts: aOR 2.60 (95% CI 0.31-21.94)
Frameshift mutations, detectable PAH-DNA adducts: aOR 4.85 (95% CI 0.62-37.75)
Results Comments
Authors note inconsistencies in PAH exposure and p53 mutations associations across studies, which they say may be due to differences in age and race distributions, PAH metabolism, and incomplete measures of exposure. Additional differences across studies may result from unmeasured activities of other repair genes and mechanisms as a response to PAH exposure.
Authors note inconsistencies in PAH exposure and p53 mutations associations across studies, which they say may be due to differences in age and race distributions, PAH metabolism, and incomplete measures of exposure. Additional differences across studies may result from unmeasured activities of other repair genes and mechanisms as a response to PAH exposure.
Abstract
BACKGROUND: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology.Objectives: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. METHODS: We examined this possibility in a population-based case-control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. RESULTS: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH-DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation-negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11-2.15] but not p53 mutation-positive (OR = 0.77; 95% CI, 0.43-1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C-->A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. CONCLUSIONS: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation.
BACKGROUND: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology.Objectives: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. METHODS: We examined this possibility in a population-based case-control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. RESULTS: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH-DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation-negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11-2.15] but not p53 mutation-positive (OR = 0.77; 95% CI, 0.43-1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C-->A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. CONCLUSIONS: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation.
Author address
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599-7435, USA. irinam@email.unc.edu
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599-7435, USA. irinam@email.unc.edu
Controls participation rate
63% completed interview 46% both completed intervi
63% completed interview 46% both completed intervi
Reviewers Comments
p53 mutation subgroups may warrant further analysis in breast cancer studies.
p53 mutation subgroups may warrant further analysis in breast cancer studies.