Table_6_Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications.DOCX

Triple-negative breast cancer (TNBC) accounts for ~15–20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.

三阴性乳腺癌（Triple-negative breast cancer, TNBC）约占乳腺癌（Breast cancer, BC）的15%~20%，相较于其他乳腺癌亚型，其早期复发率与死亡率均更高。趋化因子（C-C基序）配体5（Chemokine (C-C motif) ligand 5, CCL5）及其信号通路已被证实与三阴性乳腺癌相关。本研究旨在探讨CCL5信号通路相关基因的遗传变异对三阴性乳腺癌的易感性及预后影响。本研究对1082名无亲缘关系的突尼斯受试者（544名乳腺癌患者，其中196名为三阴性乳腺癌患者，以及538名健康对照）的CCL5及其他6个CCL5信号通路基因（CCND1、ZMIZ1、CASP8、NOTCH2、MAP3K21、HS6ST3）的变异进行了分型；评估了上述变异与乳腺癌特异性总生存期（Overall Survival, OVS）及无进展生存期（Progression-Free Survival, PFS）的关联；并分析了CCL5 mRNA及血清水平与CCL5基因型的相关性。研究结果显示：CCND1 rs614367-TT基因型（比值比OR=5.14；P=0.004）与三阴性乳腺癌风险存在极显著关联，同时rs614367-T等位基因与三阴性乳腺癌患者的无进展生存期缩短存在显著关联。MAP3K21 rs1294255-C等位基因，尤其是rs1294255-GC基因型（OR=0.47；P=0.001），与淋巴结转移风险降低相关。CCL5变异位点rs2107538与rs2280789与CCL5血清及mRNA水平存在关联。在TCGA三阴性乳腺癌/基底样队列中，MAP3K21 rs1294255-G等位基因与总生存期缩短相关。乳腺肿瘤中CCL5高表达与所有乳腺癌患者的总生存期延长显著相关，这一关联在三阴性乳腺癌/基底样患者中尤为显著。综上，CCL5信号通路相关基因的遗传变异不仅可预测三阴性乳腺癌的发病风险，还可提示疾病的侵袭性。