Environment and Breast Cancer: Science Review
About
Polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study
White, A. J., Chen, J., McCullough, L. E., Xu, X., Cho, Y. H., Teitelbaum, S. L., Neugut, A. I., Terry, M. B., Hibshoosh, H., Santella, R. M., Gammon, M. D. Cancer Causes Control. 2015. 26:12, 1791-802.
Topic area
Environmental pollutant - PAHs
Environmental pollutant - PAHs
Study design
Population-based case-control
Population-based case-control
Funding agency
NIH Department of Defense
NIH Department of Defense
Study Participants
Number of Cases
873
873
Menopausal Status
The menopausal status of women included in this study is listed here.
No analyses 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). 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. For gene-specific analyses, sample sizes further limited to those cases (439-479 cases) who had promoter methylation assessed for each gene-specific analysis.
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.
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.
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. Promoter methylation status was measured in tumor
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. Promoter methylation status was measured in tumor
How exposure was measured
Biological
Biological
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. Treatment status of cases not specified, but in overall LIBCSP, serum obtained from 77% of cases prior to chemotherapy initiation.
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. Treatment status of cases not specified, but in overall LIBCSP, serum obtained from 77% of cases prior to chemotherapy initiation.
Breast cancer outcome investigated
Primary incident breast cancer
Primary incident breast cancer
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.
Age at diagnosis, age at menarche, BMI, lactation, income, active/passive smoking history, and average lifetime intake of grilled and smoked food.
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
Association between detectable vs non-detectable PAH-DNA adducts and breast cancer, by gene-specific methylation status:
RARB:
Unmethylated: aOR 1.24 (95% CI 0.93-1.66)
Methylated: aOR 1.24 (95% CI 0.81-1.90)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 2.69 (95% CI 1.02-7.12)
p-interaction: 0.03
APC:
Unmethylated: aOR 1.41 (95% CI 1.01-1.97)
Methylated: aOR 1.24 (95% CI 0.89-1.72)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.76 (95% CI 0.87-3.58)
p-interaction: 0.09
GSTP1:
Unmethylated: aOR 1.35 (95% CI 1.00-1.81)
Methylated: aOR 1.04 (95% CI 0.69-1.56)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.62 (95% CI 0.65-4.05)
ESR1:
Unmethylated: aOR 1.21 (95% CI 0.88-1.65)
Methylated: aOR 1.39 (95% CI 0.98-1.95)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.12 (95% CI 0.53-2.38)
PGR:
Unmethylated: aOR 1.30 (95% CI 1.00-1.69)
Methylated: aOR 1.30 (95% CI 0.69-2.45)
BRCA1:
Unmethylated: aOR 1.35 (95% CI 0.94-1.93)
Methylated: aOR 1.25 (95% CI 0.92-1.69)
Case only --
Unmethylated ER+PR+ tumors vs all other unmethylated tumors: aROR 1.23 (95% CI 0.58-2.65)
H1N1:
Unmethylated: aOR 1.61 (95% CI 1.06-2.43)
Methylated: aOR 1.09 (95% CI 0.81-1.46)
Case only --
Methylated vs unmethylated tumors: aROR 0.66 (95% CI 0.42-1.05)
RASSF1A:
Unmethylated: aOR 1.06 (95% CI 0.59-1.92)
Methylated: aOR 1.27 (95% CI 0.97-1.67)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.18 (95% CI 0.68-2.04)
DAPK:
Unmethylated: aOR 1.28 (95% CI 0.97-1.69)
Methylated: aOR 1.03 (95% CI 0.60-1.76)
Case only --
Unmethylated ER+PR+ tumors vs all other unmethylated tumors: aROR 1.20 (95% CI 0.69-2.12)
CCND2:
Unmethylated: aOR 1.27 (95% CI 0.96-1.67)
Methylated: aOR 1.08 (95% CI 0.64-1.80)
TWIST:
Unmethylated: aOR 1.22 (95% CI 0.93-1.60)
Methylated: aOR 1.45 (95% CI 0.80-2.60)
Case only --
Unmethylated ER+PR+ tumors vs all other unmethylated tumors: aROR 1.17 (95% CI 0.67-2.03)
CDH1:
Unmethylated: aOR 1.28 (95% CI 0.98-1.66)
Methylated: aOR 0.87 (95% CI 0.37-2.07)
Association between global methylation markers and detectable PAH-DNA adducts among controls:
LINE-1, ≥78.7% vs <78.7% methylated: aOR 1.25 (95% CI 0.94-1.65)
LUMA, ≥0.56% vs <0.56% methylated: aOR 0.92 (95% CI 0.70-1.22)
Association between detectable vs non-detectable PAH-DNA adducts and breast cancer, by gene-specific methylation status:
RARB:
Unmethylated: aOR 1.24 (95% CI 0.93-1.66)
Methylated: aOR 1.24 (95% CI 0.81-1.90)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 2.69 (95% CI 1.02-7.12)
p-interaction: 0.03
APC:
Unmethylated: aOR 1.41 (95% CI 1.01-1.97)
Methylated: aOR 1.24 (95% CI 0.89-1.72)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.76 (95% CI 0.87-3.58)
p-interaction: 0.09
GSTP1:
Unmethylated: aOR 1.35 (95% CI 1.00-1.81)
Methylated: aOR 1.04 (95% CI 0.69-1.56)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.62 (95% CI 0.65-4.05)
ESR1:
Unmethylated: aOR 1.21 (95% CI 0.88-1.65)
Methylated: aOR 1.39 (95% CI 0.98-1.95)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.12 (95% CI 0.53-2.38)
PGR:
Unmethylated: aOR 1.30 (95% CI 1.00-1.69)
Methylated: aOR 1.30 (95% CI 0.69-2.45)
BRCA1:
Unmethylated: aOR 1.35 (95% CI 0.94-1.93)
Methylated: aOR 1.25 (95% CI 0.92-1.69)
Case only --
Unmethylated ER+PR+ tumors vs all other unmethylated tumors: aROR 1.23 (95% CI 0.58-2.65)
H1N1:
Unmethylated: aOR 1.61 (95% CI 1.06-2.43)
Methylated: aOR 1.09 (95% CI 0.81-1.46)
Case only --
Methylated vs unmethylated tumors: aROR 0.66 (95% CI 0.42-1.05)
RASSF1A:
Unmethylated: aOR 1.06 (95% CI 0.59-1.92)
Methylated: aOR 1.27 (95% CI 0.97-1.67)
Case only --
Methylated ER+PR+ tumors vs all other methylated tumors: aROR 1.18 (95% CI 0.68-2.04)
DAPK:
Unmethylated: aOR 1.28 (95% CI 0.97-1.69)
Methylated: aOR 1.03 (95% CI 0.60-1.76)
Case only --
Unmethylated ER+PR+ tumors vs all other unmethylated tumors: aROR 1.20 (95% CI 0.69-2.12)
CCND2:
Unmethylated: aOR 1.27 (95% CI 0.96-1.67)
Methylated: aOR 1.08 (95% CI 0.64-1.80)
TWIST:
Unmethylated: aOR 1.22 (95% CI 0.93-1.60)
Methylated: aOR 1.45 (95% CI 0.80-2.60)
Case only --
Unmethylated ER+PR+ tumors vs all other unmethylated tumors: aROR 1.17 (95% CI 0.67-2.03)
CDH1:
Unmethylated: aOR 1.28 (95% CI 0.98-1.66)
Methylated: aOR 0.87 (95% CI 0.37-2.07)
Association between global methylation markers and detectable PAH-DNA adducts among controls:
LINE-1, ≥78.7% vs <78.7% methylated: aOR 1.25 (95% CI 0.94-1.65)
LUMA, ≥0.56% vs <0.56% methylated: aOR 0.92 (95% CI 0.70-1.22)
Results Comments
No analyses for CDKN2A because of cell sizes <5. In addition, case-only interaction analyses were not performed for CDH1, CCND2, or PGR because cell sizes < 5. No significant interaction found in case-control analysis of global methylation markers and PAH-DNA adducts, nor in case-case analysis of PAH-DNA adducts and ER+PR+ tumors vs all others within strata of global methylation makers (< vs ≥ median global methylation). Authors note that methylation-specific PCR (used to detect presence/absence of methylation for ESR1, PCR and BRCA1) is a less sensitive assay than MethyLight (used to evaluate “percent methylated” for the remaining genes). It is possible that the methylation-specific PCR method was not able to detect low levels of methylation for ESR1, PCR and BRCA1.
No analyses for CDKN2A because of cell sizes <5. In addition, case-only interaction analyses were not performed for CDH1, CCND2, or PGR because cell sizes < 5. No significant interaction found in case-control analysis of global methylation markers and PAH-DNA adducts, nor in case-case analysis of PAH-DNA adducts and ER+PR+ tumors vs all others within strata of global methylation makers (< vs ≥ median global methylation). Authors note that methylation-specific PCR (used to detect presence/absence of methylation for ESR1, PCR and BRCA1) is a less sensitive assay than MethyLight (used to evaluate “percent methylated” for the remaining genes). It is possible that the methylation-specific PCR method was not able to detect low levels of methylation for ESR1, PCR and BRCA1.
Author address
Department of Epidemiology, University of North Carolina, CB#7435, McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA. whitea@unc.edu. Departments of Preventive Medicine, Ichan School of Medicine at Mt. Sinai, New York, NY, USA. Departments of Onco
Department of Epidemiology, University of North Carolina, CB#7435, McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA. whitea@unc.edu. Departments of Preventive Medicine, Ichan School of Medicine at Mt. Sinai, New York, NY, USA. Departments of Onco
Controls participation rate
63% completed interview 46% both completed intervi
63% completed interview 46% both completed intervi