Environment and Breast Cancer: Science Review
About
Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk
Crew, K. D., Gammon, M. D., Terry, M. B., Zhang, F. F., Zablotska, L. B., Agrawal, M., Shen, J., Long, C. M., Eng, S. M., Sagiv, S. K., Teitelbaum, S. L., Neugut, A. I., Santella, R. M. Cancer Epidemiol Biomarkers Prev. 2007. 16:10, 2033-41.
Topic area
Environmental pollutant - PAHs Genetic variability
Environmental pollutant - PAHs Genetic variability
Study design
Population based case-control
Population based case-control
Funding agency
NCI NIEHS Breast Cancer Research Foundation
NCI NIEHS Breast Cancer Research Foundation
Study Participants
Number of Cases
873
873
Menopausal Status
The menopausal status of women included in this study is listed here.
No analyses by 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 were 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). The analyses reported here were limited to women for whom PAH-DNA adducts were assessed in blood samples, which is reflected in the number of cases/controls reported above. Participants for whom samples could not be genotyped (<10%), generally due to insufficient DNA, were also excluded.
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. Treatment status of cases was not specified, but in overall LIBCSP, serum obtained from 77% of cases prior to chemotherapy initiation.
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. Treatment status of cases was not specified, but in overall LIBCSP, serum obtained from 77% of cases prior to chemotherapy initiation.
Exposure Investigated
Exposures investigated
PAH-DNA adducts were measured by competitive enzyme linked immunosorbent assay (ELISA) in blood samples obtained an average of 3 months after diagnosis for cases. Samples with <15% inhibition were considered non-detect. Nucleotide excision repair genes w
PAH-DNA adducts were measured by competitive enzyme linked immunosorbent assay (ELISA) in blood samples obtained an average of 3 months after diagnosis for cases. Samples with <15% inhibition were considered non-detect. Nucleotide excision repair genes w
How exposure was measured
Biological Questionnaire, in person
Biological Questionnaire, in person
Exposure assessment comment
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. The genes considered are all involved in nucleotide excision repair (NER). XPD gene produces a DNA helicase with roles in NER, cell cycle control, and apoptosis. ERCC1 may affect mRNA stability.
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. The genes considered are all involved in nucleotide excision repair (NER). XPD gene produces a DNA helicase with roles in NER, cell cycle control, and apoptosis. ERCC1 may affect mRNA stability.
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.
Race, family history, history of benign breast disease, age at menarche, age at first pregnancy, parity, fertility problems, menopausal status, oral contraceptive use, HRT use, BMI, alcohol use, and smoking status.
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
ERCC1 8092C/A genotype, compared to homozygous wildtype CC, non-detectable PAH-DNA adducts:
Wildtype CC, detectable PAH-DNA adducts: OR 1.21 (95% CI 0.91-1.61)
Variant CA, detectable PAH-DNA adducts: OR 1.24 (95% CI 0.92-1.67)
Variant AA, detectable PAH-DNA adducts: OR 1.92 (95% CI 1.14-3.25)
Variant AA, detectable < median: OR 2.21 (95% CI: 1.12-4.38)
Variant AA, detectable ≥ median: OR 1.63 (95% CI: 0.79-3.36)
XPD Asp312Asn(G/A) genotype, compared to homozygous wildtype GG, non-detectable PAH-DNA adducts:
Wildtype GG, detectable PAH-DNA adducts: OR 1.45 (95% CI 1.05-2.00)
Variant GA, detectable PAH-DNA adducts: OR 1.56 (95% CI 1.13-2.15)
Variant AA, detectable PAH-DNA adducts: OR 1.83 (95% CI 1.22-2.76)
Variant AA, detectable < median: OR 1.50 (95% CI 0.89-2.53)
Variant AA, detectable ≥ median: OR 2.19 (95% CI 1.32-3.61)
ERCC1 8092C/A genotype, compared to homozygous wildtype CC, non-detectable PAH-DNA adducts:
Wildtype CC, detectable PAH-DNA adducts: OR 1.21 (95% CI 0.91-1.61)
Variant CA, detectable PAH-DNA adducts: OR 1.24 (95% CI 0.92-1.67)
Variant AA, detectable PAH-DNA adducts: OR 1.92 (95% CI 1.14-3.25)
Variant AA, detectable < median: OR 2.21 (95% CI: 1.12-4.38)
Variant AA, detectable ≥ median: OR 1.63 (95% CI: 0.79-3.36)
XPD Asp312Asn(G/A) genotype, compared to homozygous wildtype GG, non-detectable PAH-DNA adducts:
Wildtype GG, detectable PAH-DNA adducts: OR 1.45 (95% CI 1.05-2.00)
Variant GA, detectable PAH-DNA adducts: OR 1.56 (95% CI 1.13-2.15)
Variant AA, detectable PAH-DNA adducts: OR 1.83 (95% CI 1.22-2.76)
Variant AA, detectable < median: OR 1.50 (95% CI 0.89-2.53)
Variant AA, detectable ≥ median: OR 2.19 (95% CI 1.32-3.61)
Results Comments
XPD homozygous variant genotype significantly modified odds of breast cancer among women with detectable PAH-DNA adducts (multiplicative p for interaction = 0.02). No evidence of interaction between presence of adducts and variant alleles of XPA -4G/A, XPF Arg415Gln(G/A) or XPG Asp1104His(G/C.)
XPD homozygous variant genotype significantly modified odds of breast cancer among women with detectable PAH-DNA adducts (multiplicative p for interaction = 0.02). No evidence of interaction between presence of adducts and variant alleles of XPA -4G/A, XPF Arg415Gln(G/A) or XPG Asp1104His(G/C.)
Author address
Department of Epidemiology, Mailman School of Public Health, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA. kd59@columbia.edu
Department of Epidemiology, Mailman School of Public Health, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA. kd59@columbia.edu
Controls participation rate
63% completed interview 46% both completed intervi
63% completed interview 46% both completed intervi