Université Paris-Sud, Villejuif, France.
Carcinogenesis. 2012 May;33(5):1059-64. doi: 10.1093/carcin/bgs116. Epub 2012 Mar 1.
Lung cancer (LC) is the leading cause of cancer-related death worldwide and tobacco smoking is the major associated risk factor. DNA repair is an important process, maintaining genome integrity and polymorphisms in DNA repair genes may contribute to susceptibility to LC. To explore the role of DNA repair genes in LC, we conducted a multilevel association study with 1655 single nucleotide polymorphisms (SNPs) in 211 DNA repair genes using 6911 individuals pooled from four genome-wide case-control studies. Single SNP association corroborates previous reports of association with rs3131379, located on the gene MSH5 (P = 3.57 × 10-5) and returns a similar risk estimate. The effect of this SNP is modulated by histological subtype. On the log-additive scale, the odds ratio per allele is 1.04 (0.84-1.30) for adenocarcinomas, 1.52 (1.28-1.80) for squamous cell carcinomas and 1.31 (1.09-1.57) for other histologies (heterogeneity test: P = 9.1 × 10(-)(3)). Gene-based association analysis identifies three repair genes associated with LC (P < 0.01): UBE2N, structural maintenance of chromosomes 1L2 and POLB. Two additional genes (RAD52 and POLN) are borderline significant. Pathway-based association analysis identifies five repair pathways associated with LC (P < 0.01): chromatin structure, DNA polymerases, homologous recombination, genes involved in human diseases with sensitivity to DNA-damaging agents and Rad6 pathway and ubiquitination. This first international pooled analysis of a large dataset unravels the role of specific DNA repair pathways in LC and highlights the importance of accounting for gene and pathway effects when studying LC.
肺癌（LC）是全球癌症相关死亡的主要原因，而吸烟是主要相关危险因素。DNA 修复是一个重要的过程，基因组完整性的维持和 DNA 修复基因的多态性可能导致对 LC 的易感性。为了探讨 DNA 修复基因在 LC 中的作用，我们使用来自四个全基因组病例对照研究的 6911 个人的样本，对 211 个 DNA 修复基因中的 1655 个单核苷酸多态性（SNP）进行了多层次关联研究。单 SNP 关联证实了先前与基因 MSH5 上的 rs3131379 相关的关联报告（P = 3.57×10-5），并得出了相似的风险估计值。该 SNP 的效应受到组织学亚型的调节。在对数加性尺度上，每个等位基因的比值比为 1.04（0.84-1.30）腺癌、1.52（1.28-1.80）鳞状细胞癌和 1.31（1.09-1.57）其他组织学（异质性检验：P = 9.1×10-3）。基于基因的关联分析确定了与 LC 相关的三个修复基因（P < 0.01）：UBE2N、染色体 1L2 结构维持和 POLB。另外两个基因（RAD52 和 POLN）也接近显著。基于途径的关联分析确定了与 LC 相关的五个修复途径（P < 0.01）：染色质结构、DNA 聚合酶、同源重组、对 DNA 损伤剂敏感的人类疾病相关基因和 Rad6 途径和泛素化。这是首次对大型数据集进行的国际 pooled 分析，揭示了特定 DNA 修复途径在 LC 中的作用，并强调了在研究 LC 时考虑基因和途径效应的重要性。
