Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
PLoS One. 2013 Dec 4;8(12):e81999. doi: 10.1371/journal.pone.0081999. eCollection 2013.
Tumour necrosis factor-alpha (TNF-α) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-κB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion. Single nucleotide polymorphisms in TNF-α, NF-κB and its inhibitor IκB genes were shown to be associated with susceptibility and prognosis of several cancers; however, their role in esophageal squamous cell carcinoma (ESCC) is not well recognised. Therefore, in present study, we aimed to investigate association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of ESCC in northern Indian population.
We genotyped 290 ESCC patients (including 162 followed up cases) and 311 mean age, gender and ethnicity matched controls for TNFA -308G>A, NFkB1 -94ATTG ins/del and NFKBIA (-826C>T and 3'UTRA>G) polymorphisms using PCR alone or followed by RFLP and TaqMan assay.
TNFA-308GA genotype was associated with increased risk of ESCC specifically in females and in patients with regional lymph node involvement, while, NFKBIA -826CT+TT genotype conferred decreased risk of ESCC in females. Haplotypes of NFKBIA -826C>T and 3'UTRA>G polymorphisms, C-826G3'UTR and T-826A3'UTR, were associated with reduced risk of ESCC. No independent role of NFkB1 -94ATTG ins/del polymorphism in susceptibility of ESCC was found. Multi-dimensionality reduction analysis showed three factor model TNFA-308, NFKBIA-826, NFKBIA 3'UTR as better predictor for risk of ESCC. Furthermore, combined risk genotype analysis of all studied polymorphisms showed increased risk of ESCC in patients with 1-3 risk genotype compared to '0' risk genotype. Survival analysis did not show any significant prognostic effect of studied polymorphisms. However, in stepwise multivariate analysis, metastasis was found to be independent prognostic predictor of ESCC patients.
TNFA-308 and NFKBIA (-826C>T and 3'UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population.
肿瘤坏死因子-α（TNF-α）和κ轻链基因增强子核因子（NF-κB）在肿瘤发生过程中如肿瘤起始、增殖、迁移和侵袭中起着关键作用。TNF-α、NF-κB 及其抑制剂 IκB 基因的单核苷酸多态性与多种癌症的易感性和预后相关；然而，它们在食管鳞状细胞癌（ESCC）中的作用尚未得到充分认识。因此，在本研究中，我们旨在探讨 TNF-α、NFkB1 和 NFKBIA 常见多态性与印度北部人群 ESCC 风险和预后的关系。
我们对 290 例 ESCC 患者（包括 162 例随访病例）和 311 名年龄、性别和种族匹配的对照进行了 TNFA-308G>A、NFkB1-94ATTG 插入/缺失和 NFKBIA（-826C>T 和 3'UTR>G）多态性的基因分型，使用 PCR 或随后的 RFLP 和 TaqMan 分析。
TNFA-308GA 基因型与 ESCC 风险增加相关，特别是在女性和区域淋巴结受累的患者中，而 NFKBIA-826CT+TT 基因型使女性 ESCC 风险降低。NFKBIA-826C>T 和 3'UTR>G 多态性、C-826G3'UTR 和 T-826A3'UTR 单体型与 ESCC 风险降低相关。NFkB1-94ATTG 插入/缺失多态性在 ESCC 易感性中没有独立作用。多维降维分析显示，TNFA-308、NFKBIA-826、NFKBIA3'UTR 三因素模型是 ESCC 风险的更好预测因子。此外，对所有研究的多态性进行联合风险基因型分析显示，与“0”风险基因型相比，具有 1-3 个风险基因型的患者 ESCC 风险增加。生存分析未显示研究多态性有任何显著的预后影响。然而，在逐步多变量分析中，转移被发现是 ESCC 患者的独立预后预测因子。
TNF-α和 NFKBIA（-826C>T 和 3'UTR>G）多态性可能在印度北部人群 ESCC 的易感性中起作用，但在预后中不起作用。
