A collaborative study of the etiology of breast cancer subtypes in African American women: The AMBER consortium
Breast cancer is a heterogeneous disease, with at least five intrinsic subtypes defined by molecular characteristics. Tumors that express the estrogen receptor (ER+) have better outcomes than ER- tumors, due in part to the success of hormonal therapies that target ER+ tumors. The incidence of ER- breast cancer, and the subset of ER- cancers that are basal-like, is about twice as high among African American (AA) women as among US women of European descent (EA). This disparity appears to explain, in part, the disproportionately high mortality from breast cancer that occurs in AA women. Epidemiologic research on breast cancer in AA women lags behind research in EA women. Here, we review differences in the etiology of breast cancer subtypes among AA women and describe a new consortium of ongoing studies of breast cancer in AA women.
We combined samples and data from four large epidemiologic studies of breast cancer in AA women, two cohort and two case-control, creating the African American Breast Cancer Epidemiology and Risk consortium. Tumor tissue is obtained and stored in tissue microarrays, with assays of molecular markers carried out at a pathology core. Genotyping, carried out centrally, includes a whole exome SNP array and over 180,000 custom SNPs for fine-mapping of genome-wide association studies loci and candidate pathways.
To date, questionnaire data from 5,739 breast cancer cases and 14,273 controls have been harmonized. Genotyping of the first 3,200 cases and 3,700 controls is underway, with a total of 6,000 each expected by the end of the study period.
The new consortium will likely have sufficient statistical power to assess potential risk factors, both genetic and non-genetic, in relation to specific subtypes of breast cancer in AA women.
Available from: cebp.aacrjournals.org
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ABSTRACT: The effects of reproductive factors on breast cancer risk appear to differ by estrogen receptor (ER) status. Menarche and first live birth (FLB) tend to occur at younger ages in African-Americans (AAs) than European-Americans (EAs), and could play a role in breast cancer disparities. In the Women's Circle of Health Study (WCHS) a case-control study of breast cancer in EA and AA women, in-person interviews were conducted to collect epidemiological data, including reproductive histories. Data on ER status, abstracted from pathology reports, were available for 814 AA and 538 EA breast cancer cases, and were analyzed with 1015 AA and 715 EA controls to evaluate associations between subgroups and age at menarche, age at FLB and the interval between those ages. Among AA women, later age at menarche (≥14 yrs) was associated with reduced risk of both ER+ and ER-breast cancer, with odds ratios (ORs) strongest for ER- disease (OR =0.57; 95% CI, 0.37-0.88); associations were weaker and non-significant for EA women. There were no significant associations with age at FLB, but AA women with a FLB within 15 years of menarche had increased risk of ER- disease (OR=2.26; 95% CI, 1.29-3.95), with no significant associations among EAs. In the WCHS, earlier age at menarche and shorter intervals until FLB are associated with ER- breast cancer in AA women; differential distributions by race of these and other reproductive risk factors could contribute to the higher prevalence of ER - breast cancer in AA women.
Available from: Emma Viscidi
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African American (AA) women have a disproportionately high incidence of estrogen receptor-negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns also differ by race/ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes.
Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors.
ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation.
The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality.
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ABSTRACT: DNA damage recognition and repair is a complex system of genes focused on maintaining genomic stability. Recently, there has been a focus on how breast cancer susceptibility relates to genetic variation in the DNA bypass polymerases pathway. Race-stratified and subtype-specific logistic regression models were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between 22 single-nucleotide polymorphisms (SNPs) in seven bypass polymerase genes and breast cancer risk in the Carolina Breast Cancer Study, a population-based, case-control study (1,972 cases and 1,776 controls). We used SNP-set kernel association test (SKAT) to evaluate the multi-gene, multi-locus (combined) SNP effects within bypass polymerase genes. We found similar ORs for breast cancer with three POLQ SNPs (rs487848 AG/AA vs. GG; OR = 1.31, 95 % CI 1.03-1.68 for Whites and OR = 1.22, 95 % CI 1.00-1.49 for African Americans), (rs532411 CT/TT vs. CC; OR = 1.31, 95 % CI 1.02-1.66 for Whites and OR = 1.22, 95 % CI 1.00-1.48 for African Americans), and (rs3218634 CG/CC vs. GG; OR = 1.29, 95 % CI 1.02-1.65 for Whites). These three SNPs are in high linkage disequilibrium in both races. Tumor subtype analysis showed the same SNPs to be associated with increased risk of Luminal breast cancer. SKAT analysis showed no significant combined SNP effects. These results suggest that variants in the POLQ gene may be associated with the risk of Luminal breast cancer.
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