Involvement of INF-γ functional single nucleotide polymorphism +874 T/A (rs2430561) in breast cancer risk

Abstract

According Global Cancer Statistics 2020 GLOBOCAN estimates female breast cancer was found as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), and the fourth leading cause (6.9%) of cancer death among women worldwide. Identification of new diagnostic marker sharply characterize the tumor feature is intensive need. The present work was performed to investigate the involvement of the INF-γ + 874 T/A gene polymorphism in different breast cancer prognostic factors. Polymorphism detection analysis was performed on 163 subjects from breast cancer patients, 79 with inflamed cells of breast patients and 144 controls. The gene polymorphism was detected using the amplification refractory mutation system- polymerase chain reaction method (ARMS-PCR). The distribution of INF-γ T + 874A gene polymorphism shows strong significant association between INF-γ + 874 T/A genotypes TT in BC patients (ORTT: 6.41 [95% CI = 2.72-15.1] P < 0.0001) as well as strong significant association regarding T allele (ORT: 1.99 [95% CI = 1.43-2.76] P < 0.0001) when compared to the healthy control. In ICB group the strong association was noted with INF-γ + 874 T/A genotypes AT genotype (ORAT: 2.28 [95% CI = 1.22-4.29] P = 0.007). From the different histological BC hormonal markers the human epidermal growth factor receptor 2 (HER2) was showing significant association in INF-γ + 874 T/A genotypes TT (P = 0.03) and recessive model (TT versus AA + AT P = 0.03). Concerning different BC prognostic models, the poor prognostic one of luminal B, (ER^+ve PR^+ve Her2^+ve) show significant association in the host INF-γ + 874 T/A genotype (TT, P = 0.03) and recessive model (TT versus AA + AT P = 0.02) when compared to the good prognostic hormonal status luminal A model, (ER^+ve PR^+ve Her2-ve). It seems that this is the first study that interested in correlate the INF-γ + 874 T/A gene polymorphisms in Egyptian BC patients. T allele, TT genotype and recessive model of the INF-γ + 874 T/A gene variants were documented as risk factors for BC pathogenesis. It may be used as practical biomarker to guide the BC carcinogenesis and risk process.

Keywords: ARMS-PCR, amplification refractory mutation system, polymerase chain reaction method; BC, Breast cancer; Breast cancer; C, controls; CD, cluster of differentiation; CI, 95% confidence intervals; ER, estrogen receptor; GPI, good prognostic index; Genotypes; HER2, human epidermal growth factor receptor 2; ICB, inflamed cells of breast; IL, interleukin; INF-γ; INF-γ, Interferon-γ; IRB, Institutional Review Board; ISGs, INF-stimulated genes; MPI, moderate prognostic index; NK, natural killer cells; NPI, the mandatory prognostic index; OR, odds ratio; PAM50, Prediction Analysis of Microarray 50; PPI, poor prognostic index; PR, progesterone receptor; Polymorphism; Risk factor; SNPs, single nucleotide polymorphism; TGF-β, transforming growth factor-β; TNBC, Triple Negative BC; TNF-α, tumor necrosis factor-α; Th1, T helper1.

Fig. 1

Agarose gel electrophoresis of the INF-γ (+874 T/A) different genotypes. The band of each A or T allele was detected at 263 bp. Lane L indicate DNA Ladder 100 bp marker (vivantis, Malaysia), each genotype represented with two lanes, one for A allele and the other one is for T allele. AA genotype indicated in sample # 20, 31 and 33 where A allele bands are the only present. TT genotype indicated in sample # 21, 25, 26, 34 and 35 where T allele band is the only present and AT genotype indicated in the rest of the samples where both allele bands are present. Negative control water (w) from each allele represents no band in each allele.