Shu Xiang, Purdue Mark P, Ye Yuanqing, Wood Christopher G, Chen Meng, Wang Zhaoming, Albanes Demetrius, Pu Xia, Huang Maosheng, Stevens Victoria L, Diver W Ryan, Gapstur Susan M, Virtamo Jarmo, Chow Wong-Ho, Tannir Nizar M, Dinney Colin P, Rothman Nathaniel, Chanock Stephen J, Wu Xifeng
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Oncotarget. 2015 Feb 28;6(6):4097-109. doi: 10.18632/oncotarget.3001.
We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P(meta-analysis) = 9.15 × 10⁻⁴, P(heterogeneity) = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 × 10⁻⁶). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.
我们进行了多水平分析，以确定肾细胞癌（RCC）潜在的易感基因座，这些基因座在传统的全基因组关联研究（GWAS）中可能被忽视。利用一个由894例RCC病例和1516例对照组成的GWAS数据集，使用GenGen、SNP比率检验和ALIGATOR进行基因集富集分析。抗原加工和呈递途径始终具有显著性（P值分别为0.001、0.004和<0.001）。将通用的基于基因的关联研究方法应用于排名靠前的途径，并确定驱动基因。通过比较RCC肿瘤组织和相邻正常组织中基因的表达，我们观察到肿瘤组织中HLA基因显著过表达，这也得到了公共数据库的支持。我们试图在一个由美国国立癌症研究所的1311例RCC病例和3424例对照受试者组成的独立GWAS数据集中验证抗原加工和呈递途径中的基因变异；一个单核苷酸多态性（SNP），rs1063355，在两个群体中均具有显著性（P（meta分析）=9.15×10⁻⁴，P（异质性）=0.427）。强相关性表明rs1063355是一个与HLA-DQB1表达相关的顺式表达数量性状基因座（斯皮尔曼等级相关系数r=-0.59，p=5.61×10⁻⁶）。使用一个公共数据集进一步验证了这种相关性。我们的结果突出了免疫相关途径和基因在RCC病因学中的作用。
