Enjuanes Anna, Benavente Yolanda, Bosch Francesc, Martín-Guerrero Idoia, Colomer Dolors, Pérez-Alvarez Susana, Reina Oscar, Ardanaz Maria T, Jares Pedro, García-Orad Africa, Pujana Miguel A, Montserrat Emili, de Sanjosé Silvia, Campo Elias
Department of Anatomic Pathology, Hematopathology Section, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Cancer Res. 2008 Dec 15;68(24):10178-86. doi: 10.1158/0008-5472.CAN-08-2221.
To identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), we performed a case-control study genotyping 768 single-nucleotide polymorphisms (SNP) in 692 cases of CLL and 738 controls. We investigated nonsynonymous SNPs, SNPs with potential functional effect, and tag SNPs in regulatory gene regions in a total of 172 genes involved in cancer biology. After adjustment for multiple testing, we found a strong association between CLL risk and six genetic variants: CCNH (rs2266690, V270A), APAF1 (rs17028658, 3'region), IL16 (rs4505265, first intron), CASP8 (rs1045485, D302H), NOS2A (rs2779251, promoter), and CCR7 (rs3136687, intron 1). We found association with CLL susceptibility and 22 haplotypes in APAF1, IL6, TNFRSF13B, IL16, CASP3, CCR7, LTA/TNF, BAX, BCL2, CXCL12, CASP10/CASP8, CASP1, CCL2, BAK1, and IL1A candidate genes. Finally, we evaluated using public data sets the potential functional effect on gene expression levels of the CLL associated genetic variants detected in regulatory regions. Minor alleles for APAF1 and IL16 were associated with lower mRNA levels; no expression differences were observed for CCR7, whereas NOS2A could not be assessed. This study suggests that common genetic variation in apoptosis- and immunoregulation-related genes is associated with the CLL risk.
为了鉴定慢性淋巴细胞白血病（CLL）的低 penetrance 易感性等位基因，我们开展了一项病例对照研究，对 692 例 CLL 患者和 738 例对照进行了 768 个单核苷酸多态性（SNP）的基因分型。我们研究了总共 172 个参与癌症生物学的基因中的非同义 SNP、具有潜在功能效应的 SNP 以及调控基因区域中的标签 SNP。在对多重检验进行校正后，我们发现 CLL 风险与六个基因变异之间存在强关联：CCNH（rs2266690，V270A）、APAF1（rs17028658，3'区域）、IL16（rs4505265，第一内含子）、CASP8（rs1045485，D302H）、NOS2A（rs2779251，启动子）和 CCR7（rs3136687，内含子 1）。我们发现与 CLL 易感性以及 APAF1、IL6、TNFRSF13B、IL16、CASP3、CCR7、LTA/TNF、BAX、BCL2、CXCL12、CASP10/CASP8、CASP1、CCL2、BAK1 和 IL1A 候选基因中的 22 个单倍型相关。最后，我们使用公共数据集评估了在调控区域中检测到的与 CLL 相关的基因变异对基因表达水平的潜在功能影响。APAF1 和 IL16 的次要等位基因与较低的 mRNA 水平相关；未观察到 CCR7 的表达差异，而 NOS2A 无法进行评估。这项研究表明，凋亡和免疫调节相关基因的常见遗传变异与 CLL 风险相关。
