State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Carcinogenesis. 2012 Jan;33(1):94-100. doi: 10.1093/carcin/bgr228. Epub 2011 Oct 19.
Copy number variations (CNVs) have been recognized to contribute to phenotypic variations and to be associated with susceptibility to certain complex diseases. This study examined the functional significance of CNVR2966.1 at 6q13 and its association with pancreatic cancer susceptibility. The CNVR2966.1 was found to be a 10,379 bp nucleotides deletion/insertion within the uniform boundaries chromosome 6: 74 648 791-74 659 169. Luciferase reporter gene assays revealed an active regulator in CNVR2966.1, which was demonstrated by circular chromosome conformation capture assays to physically interact with the upstream functional sequence of CDKN2B. CDKN2B transcription levels in pancreatic tissues were therefore significantly higher in individuals with two copies of CNVR2966.1 than in those with low copy number of CNVR2966.1. The risk of pancreatic cancer observed in 1027 cases and 1031 controls was significantly associated with copy number of CNVR2966.1, with the odds ratio being 1.31 (95% confidence interval = 1.08-1.60; P = 0.007) for one copy genotype compared with two copies genotype. These results suggest that CNVR2966.1 is associated with pancreatic cancer risk probably owing to its effect on long-range regulation of CDKN2B.
拷贝数变异 (CNVs) 已被认为导致表型变异，并与某些复杂疾病的易感性相关。本研究检测了 6q13 上的 CNVR2966.1 的功能意义及其与胰腺癌易感性的关联。发现 CNVR2966.1 是均匀边界染色体 6 内的 10,379 个核苷酸缺失/插入：74648791-74659169。荧光素酶报告基因检测显示 CNVR2966.1 内存在一个活性调节剂，通过环形染色体构象捕获检测证实其与 CDKN2B 的上游功能序列发生物理相互作用。因此，携带 CNVR2966.1 两个拷贝的个体的胰腺组织中 CDKN2B 的转录水平明显高于携带低拷贝数 CNVR2966.1 的个体。在 1027 例病例和 1031 例对照中观察到的胰腺癌风险与 CNVR2966.1 的拷贝数显著相关，与低拷贝数相比，单拷贝基因型的比值比为 1.31（95%置信区间 = 1.08-1.60；P = 0.007）。这些结果表明，CNVR2966.1 与胰腺癌风险相关，可能是由于其对 CDKN2B 的长距离调控的影响。
