Shan Jingxuan, Chouchane Aziz, Mokrab Younes, Saad Mohamad, Boujassoum Salha, Sayaman Rosalyn W, Ziv Elad, Bouaouina Noureddine, Remadi Yasmine, Gabbouj Sallouha, Roelands Jessica, Ma Xiaojing, Bedognetti Davide, Chouchane Lotfi
Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, United States.
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States.
Front Oncol. 2019 Dec 6;9:1328. doi: 10.3389/fonc.2019.01328. eCollection 2019.
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 and that of six other CCL5 signaling genes () 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 genotypes. We found a highly significant association between the genotype (OR = 5.14; = 0.004) and TNBC risk, and identified a significant association between the allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the allele, particularly in (OR = 0.47; = 0.001). variants ( and ) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the allele was associated with a decreased OVS. High expression of 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（TNBC）约占乳腺癌（BC）的15 - 20%，与其他亚型相比，其早期复发率和死亡率更高。趋化因子（C - C基序）配体5（CCL5）及其信号通路与TNBC有关。在本研究中，我们旨在调查TNBC中CCL5信号基因遗传变异的易感性及其预后意义。我们对1082名不相关的突尼斯受试者（544例BC患者，包括196例TNBC患者，以及538名健康对照）中的CCL5基因及其它六个CCL5信号基因的变异进行了特征分析，评估了这些变异与BC特异性总生存期（OVS）和无进展生存期（PFS）的相关性，并将CCL5 mRNA和血清水平与基因分型相关联。我们发现基因型与TNBC风险之间存在高度显著的关联（OR = 5.14；= 0.004），并确定等位基因与TNBC患者PFS降低之间存在显著关联。等位基因与淋巴结转移风险降低相关，尤其是在中（OR = 0.47；= 0.001）。变异（和）与CCL5血清和mRNA水平相关。在TCGA TNBC/基底样队列中，等位基因与OVS降低相关。在所有BC患者中，尤其是TNBC/基底样患者中，乳腺肿瘤中高表达与OVS增加显著相关。总之，CCL5信号基因的遗传变异不仅可以预测TNBC风险，还可以预测疾病的侵袭性。
