The African-Specific Variant in the Duffy Antigen Receptor for Chemokines Gene, CD8+ T-Cell Density, and Aggressive Breast Cancer Subtypes in Black Women.

Background: Immune response in blood varies by ancestry, linked to an African-specific variant (rs2814778) in the Duffy Antigen Receptor for Chemokines (DARC/ACKR1) gene. We examined associations between rs2814778, CD8+ T-cell density in breast tumors, and breast cancer risk in African-American/Black women.

Methods: CD8+ T-cell density in tumors from 428 Black women were examined in relation to the rs2814778 variant. In the African Ancestry Breast Cancer Genetics (AABCG) Consortium with 16,886 cases and 18,044 controls, rs2814778 was evaluated in relation to risk of overall breast cancer and to more aggressive subtypes [estrogen receptor-negative (ER-) and triple-negative breast cancer (TNBC)].

Results: Women with the African-specific CC genotype had lower tumor CD8+ T-cell density (87.0 per mm2) than those with TT genotypes (146.6 per mm2; P < 0.05). Each T allele was significantly associated with an increase in T-cell density (P = 0.04). In the largest analysis, to date, there were no associations between rs2814778 and risk of overall breast cancer [OR = 0.90 (95% confidence interval (CI), 0.66-1.22)] or with ER- breast cancer [OR = 0.86 (95% CI, 0.68-1.08)] or TNBC [OR = 0.77 (95% CI, 0.56-1.05)].

Conclusions: Although breast tumors from women with the African-specific DARCC allele had lower CD8+ T-cell density levels than those with T alleles, in a large breast cancer consortium with adequate statistical power, the variant was not associated with breast cancer risk overall, nor with risk of ER- breast cancer or TNBC, as previously hypothesized.

Impact: Although the "Duffy-null" allele has been the focus of research as a contributor to aggressive breast cancer in Black women, this study with 34,930 cases and controls found no associations with risk.