Milne Roger Laughlin, Ribas Gloria, González-Neira Anna, Fagerholm Rainer, Salas Antonio, González Emilio, Dopazo Joaquín, Nevanlinna Heli, Robledo Mercedes, Benítez Javier
National Genotyping Centre, Spanish National Cancer Centre, Madrid, Spain.
Cancer Res. 2006 Oct 1;66(19):9420-7. doi: 10.1158/0008-5472.CAN-06-1418.
The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.
连锁研究未能进一步鉴定出乳腺癌的高 penetrance 易感性基因，这表明多基因模型是最有可能的候选模型，即更常见的变异对风险有适度影响。我们在两个欧洲人群中开展了一项两阶段病例对照研究，以使用高通量基因分型鉴定乳腺癌的低 penetrance 基因。在预先选定的癌症相关基因中选择单核苷酸多态性（SNP），尽可能选择标签 SNP 和功能变异。在第一阶段，比较了来自西班牙人群的 864 例乳腺癌病例和 845 例对照中 111 个基因的 640 个 SNP 的基因型频率。在第二阶段，对在第一阶段鉴定出的候选 SNP（名义 P < 0.01）在芬兰的 884 例病例和 1104 例对照系列中进行测试。在第一阶段鉴定出的七个基因中的 10 个候选 SNP 中，ERCC4（属于核苷酸切除修复途径的一个基因）内含子 1 上的一个 SNP（rs744154）在第二阶段经过多重检验校正后与对乳腺癌的隐性保护相关（优势比，0.57；Bonferroni 校正 P = 0.04）。在考虑了跨越整个基因并向上游延伸至启动子区域的高连锁不平衡区域中的潜在功能 SNP 后，我们得出结论，rs744154 本身可能是因果性的。尽管它是内含子的，但它位于第一个内含子上，在一个跨物种高度保守的区域，因此可能在功能上很重要。这项研究表明 ERCC4 中常见的内含子变异与对乳腺癌的保护相关。
