The present study represents the first genome-wide admixture scan conducted in African American women with breast cancer. In this study, we did not find an association between breast cancer risk and African or European ancestry at any specific loci among all cases or within subtypes of breast cancer, at genome-wide levels of significance. We did detect European ancestry to be over-represented among women with ER+ tumors. However, adjustment for known breast cancer risk factors could explain this association. A significant association remained for ER+PR+ tumors following adjustment, which could be due to misclassification of these risk factors, or, other risk factors which we did not consider (e.g., alcohol consumption) or that we do not know about that do correlate with ancestry and influence tumor characteristics. At the same time, it is possible that this association is due to genetic risk factors that correlate with ancestry. We observed that nulliparity was associated with both ER+PR+ disease as well as European ancestry. The association between number of full term pregnancies and hormone receptors status has been reported before in African Americans and white women (29
) and our data replicates these results. The association between nulliparity and ER+PR+ disease could be the result of an underlying biological mechanism or could be due to the correlation between this risk factor and other known or unknown risk factors that we did not account for. The association between European ancestry and nulliparity was also significant (p=0.01) but could not completely explain the association that we observed between ancestry and ER/PR status. We also detected European ancestry to be significantly over-represented among women with localized tumors compared to women with non-localized tumors (2.65, 95% CI: 1.11–6.35, p=0.029). This association could not be explained by the known breast cancer risk factors.
The exclusion map shows that for the analysis of the ER− cases we had reasonable power to detect an increased risk due to an African allele of 1.8 and above and an increased risk due to a European allele of 1.6 and above. Therefore, the fact that our scan did not detect any significant signal does not discard the possibility that ancestry effects of 1.7 or lower are present. The observed association between ancestry and ER/PR status supports this possibility and suggests that further analyses are needed with adequate power to detect ancestry effects on risk of 1.7 or less.
We detected a non-significant deviation towards higher African ancestry on chromosome 10q26 compared to the chromosomal average. This region includes the FGFR2
gene and a common variant that is associated with increased risk of breast cancer in Asian and European populations (33
). A recently published study investigated FGFR2 variants in African Americans, Asians and Europeans in order to search for causative variants and to evaluate if the same variants were associated with risk of breast cancer in the different racial/ethnic groups (38
). Based on association results and an analysis of DNase I hypersensitive sites looking at chromatin accessibility the conclusion was reached that two variants, rs2981578 and rs10736303, are the most likely to be causal variants. The frequency of these two variants is different in African populations compared to Europeans or Asians. The frequency of the risk allele for the variant rs2981578 is 0.93 in the HapMap African sample and 0.46 in the HapMap Europeans. A similar difference is observed for the rs10736303, with the risk allele having a frequency of 0.92 in Africans and 0.60 in Europeans2
. The increase in African ancestry that we observed in the admixture mapping analysis within the 10q26 region could potentially be explained by the higher frequency of causal risk alleles in this region which are likely to be more common in African than European populations.
There was no apparent deviation from the average chromosomal ancestry for any other region of the genome previously reported to have a risk variant. Different studies have reported associations between variants in the FGFR2 gene and breast cancer risk, with per-allele ORs that vary between 1.20 and 1.30 (33
). The reported ORs for the FGFR2 gene are among the higher reported ORs compared to those of other risk variants discovered though whole genome association studies (~1.25 compared to less than 1.20 (39
)). Adding to this, the candidate variants within the FGFR2 gene show a large allele frequency difference between Europeans and Africans. Therefore, it is likely that we did not observe any other ancestry deviations because of lack of power (We had power above 80% to detect risk variants with an allele effect of 1.5 or larger. If the allele effect was ~1.2, then the allele frequency difference between the ancestral populations needed to be larger than 0.7 to achieve a power above 40%).
One limitation of this study is the sample size. Although the study included over 1,400 women, ER−PR− cases are still a minority of cases, even among African Americans, and thus, we had limited power to assess associations for the different breast cancer phenotypes.
Her2 status was not available for the majority of cases since most of the cases in the different studies were recruited at a time when Her2 status was not routinely assayed for clinical testing. Therefore, we were unable to analyze ER−PR−Her2- negative breast cancer cases (i.e., “triple-negatives”), an aggressive subset of tumors that has been estimated to be more common in African Americans than in European Americans (28
). Much larger studies in African populations, with available tumor specimen resources for tumor phenotyping, will be needed to evaluate the genetic contribution to the various breast cancer subtypes.
Information about ER and PR status, grade and stage, comes from pathology reports or from the cancer registry, depending on the study. Therefore, it is likely that there were differences in how the tumors were classified. This potential misclassification could have contributed to the negative results observed. However, the frequency of the different tumor characteristics in the 6 studies are similar and when they differ they do it in the expected direction given the age distribution of the women in the studies. This suggests that misclassification might not be a serious problem for these data, though caution must be taken in the interpretation of the results. Future studies involving centralized tumor marker data collection will be necessary to avoid the potential effect of misclassification in genetic epidemiology studies with multiple data sources.
The AIMs selected to infer genetic ancestry are assumed to have homogenous frequency within the African continent. Given that African Americans are likely to have a mixed ancestry from different regions of Western Africa (42
) which might not shared the same allele frequencies for the markers used in the present study, results must be interpreted with caution.
The clinical implications of the differences in tumor presentation of African American women with breast cancer compared to European American patients are substantial. Although the overall incidence of breast cancer is lower in African American women, the mortality rate is higher in African American women than in European American women (43
). This may be in part due to higher rates of ER− disease, since hormonal treatment, either with selective estrogen receptor modifiers (tamoxifen or raloxifene) or with aromatase inhibitors, is highly effective for ER+ disease only (44
). Furthermore, ER− disease often occurs in younger women who have never had screening because they are younger than the standard screening age and because screening with mammography is less sensitive among younger women (45
). The high rates of ER− disease among African Americans may also have implications for breast cancer prevention. Tamoxifen and raloxifene have been shown to prevent ER+ breast cancer in primary prevention studies and some have advocated that the medications be used in high risk women (44
). In addition, aromatase inhibitors may also be useful in prevention of breast cancer (47
). However, there is no clear preventive strategy for ER− breast cancers. Identifying the causal factors that explain the difference in incidence of hormone receptor negative tumors between European American and African American women should be a high priority.
The present admixture mapping scan in 1,484 African American women with breast cancer suggests that the difference in breast cancer risk between Europeans and African Americans is unlikely to be due to an effect of a European or African allele on risk larger than 1.7. It also excludes an effect on risk for ER+ status larger than 1.9 and for ER− status larger than 2.4. Global ancestry association results, however, show a positive association of European ancestry with stage of disease, and with ER+PR+ disease. These associations could result from population differences in non-genetic risk factors or from the effect of multiple genetic variants each with a relatively moderate contribution to the ancestry related risk difference