Laboratory of DNA Polymorphisms and Immunology, Department of Pathological Sciences, Londrina State University, Londrina, Parana, Brazil.
Department of General Biology, Londrina State University, Londrina, Parana, Brazil.
Cytokine. 2018 Mar;103:121-126. doi: 10.1016/j.cyto.2017.09.019. Epub 2017 Sep 28.
Interleukin-7 (IL-7) exerts crucial functions on lymphoid cells' development and maintenance. In breast cancer (BC), IL-7 promotes growth of tumor cells in culture through the activation of JAK1/3-STAT5 and PI3K/AKT pathways, and expression of IL-7 signaling components was associated with worst prognosis. AC>T polymorphism (rs6897932; Thr244Ile) at exon 6 of IL-7 receptor alpha (IL-7Rα) gene (IL7RA) shifts the balance between the membrane-bound and soluble IL-7Rα splicing variants and was previously associated with autoimmune diseases, but has not been studied in cancer, including BC, so far. Therefore, the present study aimed to investigate the possible association of this polymorphism with the susceptibility and clinicopathological parameters of BC subgroups. IL7RA Thr244Ile was genotyped through PCR-RFLP in 403 women without neoplasia, no personal history of malignancy or family history of BC and in 338 BC patients with clinicopathological data available. BC patients were stratified according to their positivity for estrogen (ER) and/or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Age-adjusted logistic regression was performed for case-control analyses, and correlations with clinicopathological parameters were assessed through Kendall's Tau-b coefficient. All analyses were two-tailed and had 95% confidence interval. In ERPRHER2 BCs, TT genotype was associated with increased susceptibility both in genotypic (TT vs. CC: OR=3.07; CI=1.01-9.38; p=0.05) and recessive (TT vs. CC+CT: OR=3.59; CI=1.19-10.85; p=0.02) models and negatively correlated with disease stage (Tau-b=-0.27; p=0.05). Whereas T allele was positively correlated with histopathological grade (Tau-b=0.29; p=0.03) and lymph node metastasis (Tau-b=0.35; p=0.02) in ER/PRHER2BCs and with Ki67 (Tau-b=0.51; p=0.008) in ERPRHER2 subgroup. These data indicate that IL-7Rα is involved in BC, and that IL7RA polymorphism may play distinct roles in breast carcinogenesis according to BC subtype, pointing this genetic variant as an interesting marker for breast carcinogenesis to be validated by further mechanistic and prospective studies with larger samples.
白细胞介素-7（IL-7）在淋巴细胞的发育和维持中发挥着至关重要的作用。在乳腺癌（BC）中，IL-7 通过激活 JAK1/3-STAT5 和 PI3K/AKT 途径促进肿瘤细胞在培养中的生长，并且 IL-7 信号传导成分的表达与最差的预后相关。IL-7 受体 alpha（IL-7Rα）基因（IL7RA）外显子 6 上的 AC>T 多态性（rs6897932；Thr244Ile）改变了膜结合和可溶性 IL-7Rα 剪接变体之间的平衡，先前与自身免疫性疾病相关，但迄今为止尚未在癌症中进行研究，包括 BC。因此，本研究旨在探讨该多态性与 BC 亚组的易感性和临床病理参数之间的可能关联。通过 PCR-RFLP 在 403 名无肿瘤、无恶性肿瘤个人史或 BC 家族史的女性和 338 名具有临床病理资料的 BC 患者中对 IL7RA Thr244Ile 进行基因分型。根据雌激素（ER）和/或孕激素受体（PR）和人表皮生长因子受体 2（HER2）的阳性情况对 BC 患者进行分层。采用 age-adjusted 逻辑回归进行病例对照分析，并通过 Kendall's Tau-b 系数评估与临床病理参数的相关性。所有分析均为双侧，置信区间为 95%。在 ERPRHER2 BC 中，TT 基因型在基因型（TT 与 CC：OR=3.07；CI=1.01-9.38；p=0.05）和隐性（TT 与 CC+CT：OR=3.59；CI=1.19-10.85；p=0.02）模型中与易感性增加相关，并且与疾病分期呈负相关（Tau-b=-0.27；p=0.05）。而在 ER/PRHER2BC 中，T 等位基因与组织病理学分级（Tau-b=0.29；p=0.03）和淋巴结转移（Tau-b=0.35；p=0.02）呈正相关，在 ERPRHER2 亚组中与 Ki67（Tau-b=0.51；p=0.008）呈正相关。这些数据表明，IL-7Rα 参与了乳腺癌的发生，并且根据乳腺癌亚型，IL7RA 多态性可能在乳腺癌发生中发挥不同的作用，这表明该遗传变异作为一种有前途的乳腺癌发生的标志物，有待进一步的机制和前瞻性研究验证，且研究样本应更大。
