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Background:Triple-negative breast cancer (TNBC) has a higher rate of early relapse and mortality compared to other types of breast cancer (BC). CCL5 and its signaling pathway have been linked to TNBC. Methods:We characterized variants in CCL5and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21 and HS6ST3) among 1,082 unrelated Arab subjects, including 196 TNBC, accessed their association with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 expression with CCL5genotypes. Results: CCND1 rs614367-TTgenotype was highly associated with the TNBC risk (OR = 5.14; P = 0.004) and the rs614367-Tallele was associated with decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5variants (rs2107538and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21rs1294255-G allele was associated with a decreased OVS. High expression of CCL5in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. Conclusion:Genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggression. Citation Format: Salha Bujassoum Al-Bader, Jingxuan Shan, David Bedognetti, Lotfi Chouchane. Genetic variants of CCL5 signaling pathway genes in susceptibility and prognosis of triple negative breast cancers in Arab population [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-10.