Goske Maruthi, Ramachander V R Vinish, Komaravalli Prasanna Latha, Rahman P Fazul, Rao Chandrasekhar, Jahan Parveen
Department of Genetics, Osmania University, Hyderabad-07, Telangana, India.
Department of Zoology, Maulana Azad National Urdu University, Gachibowli, Hyderabad-32, Telangana, India.
World J Oncol. 2017 Oct;8(5):162-170. doi: 10.14740/wjon1046w. Epub 2017 Nov 5.
Dysfunctional regulation at immune checkpoints may lead to escape of the tumor cells and gives a scope to set in the unresolved Breast cancer (BC). The major anti-tumor retort is cell-mediated response which involves T lymphocytes. CTLA-4 (Cytotoxic T lymphocyte associated protein-4) with immune suppressive function and tolerance is associated with various autoimmune diseases and cancers including BC. The present study deals with CTLA-4 gene selected polymorphisms (rs11571317 C/T and rs3087243G/A) to explore their relation with breast cancer susceptibility and progression in BC patients.
For the present case-control study, we recruited a total of 570 women which include breast cancer patients and healthy control women from south India. Blood samples were collected, genomic DNA was isolated and genotyped by using PCR-RFLP method, and the data were analysed through suitable statistics.
We observed a significant association of rs11571317 with BC in our study group, where CC genotype showed a three-fold increased risk towards BC and CT genotype to be protective. In-silico analyses strengthened our observation revealing the abolition of SP1 binding site in the CTLA-4 promoter by the mutant allele T. The CTLA-4 rs3087243 polymorphism showed an association not with the susceptibility but towards the tumor progression, where GG genotype was coupled with reduced tumor growth (OR = 0.01) and GA (OR = 6.2), AA (OR = 3.4) with increased tumor growth. The T-G haplotype was found to confer protection against breast cancer risk while C-A (OR = 3.6) and T-A (OR = 15.8) haplotypes were associated with disease progression. In-silico analysis for rs3087243 revealed change in threshold values between reference and variant sequences.
The study suggests varied roles of different polymorphisms of CTLA-4 in the aetiopathogenesis of BC. Understanding the mechanism may help in the CTLA-4 based immunotherapy for BC.
免疫检查点的功能失调可能导致肿瘤细胞逃逸，为尚未解决的乳腺癌（BC）提供了发展空间。主要的抗肿瘤反应是涉及T淋巴细胞的细胞介导反应。具有免疫抑制功能和耐受性的细胞毒性T淋巴细胞相关蛋白4（CTLA-4）与包括BC在内的各种自身免疫性疾病和癌症有关。本研究涉及CTLA-4基因选定的多态性（rs11571317 C/T和rs3087243G/A），以探讨它们与BC患者乳腺癌易感性和进展的关系。
在本病例对照研究中，我们共招募了570名女性，包括来自印度南部的乳腺癌患者和健康对照女性。采集血样，分离基因组DNA并使用PCR-RFLP方法进行基因分型，通过适当的统计学方法分析数据。
在我们的研究组中，我们观察到rs11571317与BC之间存在显著关联，其中CC基因型显示患BC的风险增加了三倍，而CT基因型具有保护作用。电子分析强化了我们的观察结果，揭示了突变等位基因T消除了CTLA-4启动子中的SP1结合位点。CTLA-4 rs3087243多态性与易感性无关，但与肿瘤进展有关，其中GG基因型与肿瘤生长减少相关（OR = 0.01），而GA（OR = 6.2）、AA（OR = 3.4）与肿瘤生长增加相关。发现T-G单倍型可降低患乳腺癌的风险而C-A（OR = 3.6）和T-A（OR = 15.8）单倍型与疾病进展相关。对rs3087243的电子分析显示参考序列和变异序列之间的阈值发生了变化。
该研究表明CTLA-4不同多态性在BC发病机制中具有不同作用。了解其机制可能有助于基于CTLA-4的BC免疫治疗。
