Center for Genome Research, Samsung Biomedical Research Institute, Seoul, Korea.
Cancer. 2011 Sep 1;117(17):4080-91. doi: 10.1002/cncr.25930. Epub 2011 Feb 24.
The objective of this was to identify functional single nucleotide polymorphisms (SNPs) in cyclin-dependent kinases (CDKs) and cyclins that are associated with risk of human cancer.
First, 45 SNPs in CDKs and cyclins were analyzed in 106 lung cancers and 108 controls for a pilot study. One SNP (reference SNP [rs] 769236, +1 guanine to adenine [G→A]) at the promoter region of cyclin A2 (CCNA2) also was analyzed in 1989 cancers (300 breast cancers, 450 colorectal cancers, 450 gastric cancers, 367 hepatocellular carcinomas, and 422 lung cancers) and in 1096 controls. Genotyping was performed using matrix-assisted laser desorption-ionization/time-of-flight mass spectrometry. Transcriptional activity of the SNP according to the cell cycle was analyzed by using a luciferase reporter assay and fluorescence-activated cell sorting analysis in NIH3T3 cells.
In the pilot study, the SNP (rs769236) was associated significantly with the risk of lung cancer. In the expanded study, multivariate logistic regression indicated that the AA homozygous variant of the SNP was associated significantly with the development of lung cancer (P < .0001; codominant model), colorectal cancer (P < .0001), and hepatocellular carcinoma (P = .02) but not with breast cancer or gastric cancer. The luciferase activity of a 300-base pair construct that contained the A allele was 1.5-fold greater than the activity of a construct with the G allele in NIH3T3 cells. The high luciferase activity of constructs that contained the A allele did not change with cell cycle progression.
The current results suggested that an SNP (rs769236) at the promoter of CCNA2 may be associated significantly with increased risk of colon, liver, and lung cancers.
本研究旨在鉴定与人类癌症风险相关的细胞周期蛋白依赖性激酶（CDKs）和细胞周期蛋白中的功能性单核苷酸多态性（SNPs）。
首先，在 106 例肺癌和 108 例对照中分析了 CDK 和细胞周期蛋白中的 45 个 SNP，作为一项初步研究。还在 1989 例癌症（300 例乳腺癌、450 例结直肠癌、450 例胃癌、367 例肝细胞癌和 422 例肺癌）和 1096 例对照中分析了细胞周期蛋白 A2（CCNA2）启动子区域的一个 SNP（参考 SNP [rs]769236，+1 鸟嘌呤到腺嘌呤 [G→A]）。采用基质辅助激光解吸/飞行时间质谱法进行基因分型。通过荧光素酶报告基因检测和 NIH3T3 细胞的荧光激活细胞分选分析，研究 SNP 对细胞周期的转录活性。
在初步研究中，该 SNP（rs769236）与肺癌风险显著相关。在扩大的研究中，多元逻辑回归表明，该 SNP 的 AA 纯合变体与肺癌（P <.0001；共显性模型）、结直肠癌（P <.0001）和肝细胞癌（P =.02）的发生显著相关，但与乳腺癌或胃癌无关。含有 A 等位基因的 300 个碱基对构建体的荧光素酶活性比含有 G 等位基因的构建体高 1.5 倍。在 NIH3T3 细胞中，含有 A 等位基因的构建体的高荧光素酶活性不会随细胞周期进程而改变。
目前的结果表明，CCNA2 启动子中的 SNP（rs769236）可能与结直肠癌、肝癌和肺癌的风险增加显著相关。
