Rai Rajani, Sharma Kiran L, Sharma Surbhi, Misra Sanjeev, Kumar Ashok, Mittal Balraj
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
Department of Surgical Oncology, KGMU, Lucknow, India.
PLoS One. 2014 Feb 28;9(2):e90264. doi: 10.1371/journal.pone.0090264. eCollection 2014.
Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk.
This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons.
The DR4 C rs20575 A rs20576 A rs6557634, G rs20575 A rs20576 G rs6557634 and G rs20575 C rs20576 G rs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 C rs20575 A rs20576 A rs6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility.
The DR4 haplotype C rs20575 A rs20576 A rs6557634 represents an important factor accounting the patients susceptibility to GBC probably due to decreased apoptosis. However, additional well-designed studies with larger sample size focusing on different ethnicities are required to further validate the results.
凋亡缺陷是癌症发生和发展的一个标志。死亡受体（DR4、FAS）及其配体（TRAIL、FASL）被认为介导细胞内主要的外源性凋亡途径。这些基因中的单核苷酸多态性（SNP）可能导致凋亡缺陷。因此，本研究旨在探讨DR4（rs20575、rs20576和rs6557634）、FAS（rs2234767）和FASL（rs763110）的功能性SNP与胆囊癌（GBC）风险的关联。
本病例对照研究纳入400例GBC患者和246例健康对照（HC）。采用Taqman基因分型检测法进行基因分型。使用SPSS 16.0版进行统计分析。使用综合Meta分析软件（版本2.0，BIOSTAT，新泽西州恩格尔伍德）进行Meta分析，以系统总结SNP与癌症风险的可能关联。使用生物信息学工具（FAST-SNP、F-SNP）对这些变异进行功能预测。在多重比较中使用错误发现率（FDR检验）。
DR4的C rs20575 A rs20576 A rs6557634、G rs20575 A rs20576 G rs6557634和G rs20575 C rs20576 G rs6557634单倍型使GBC风险增加两倍。其中，DR4的C rs20575 A rs20576 A rs6557634单倍型成为影响GBC易感性的主要因素，因为该风险不受性别或胆结石分层的调节。我们的Meta分析结果显示，DR4 rs6557634与总体癌症风险、胃肠道癌症以及白种人显著相关。我们未发现FAS和FASL的SNP与GBC易感性之间存在任何关联。
DR4单倍型C rs20575 A rs20576 A rs6557634可能是导致患者易患GBC的一个重要因素，这可能是由于凋亡减少所致。然而，需要更多针对不同种族、样本量更大的精心设计的研究来进一步验证这些结果。
