鉴定与局部晚期结直肠腺癌临床结局相关的超保守元件多态性。
Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma.
机构信息
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
出版信息
Cancer. 2012 Dec 15;118(24):6188-98. doi: 10.1002/cncr.27653. Epub 2012 Jun 6.
BACKGROUND
Ultraconserved elements (UCEs) are noncoding genomic sequences that completely identical among human, mouse, and rat species and harbor critical biologic functions. The authors hypothesized that single nucleotide polymorphisms (SNPs) within UCEs are associated with clinical outcomes in patients with colorectal cancer (CRC).
METHODS
Forty-eight SNPs within UCEs were genotyped in 662 patients with stage I through III CRC. The associations between genotypes and recurrence and survival were analyzed in patients with stage II or III CRC who received fluoropyrimidine-based adjuvant chemotherapy using a training and validation design. The training set included 115 patients with stage II disease and 170 patients with stage III disease, and the validation set included 88 patients with stage II disease and 112 patients with stage III disease.
RESULTS
Eight SNPs were associated with clinical outcomes stratified by disease stage. In particular, for patients with stage II CRC who had at least 1 variant allele of reference SNP sequence 7849 (rs7849), a consistent association with increased recurrence risk was observed in the training set (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.04-5.52), in the replication set (HR, 3.70; 95% CI, 1.42-9.64), and in a meta-analysis (HR, 2.89; 95% CI, 1.54-5.41). Several other SNPs were significant in the training set but not in the validation set. These included rs2421099, rs16983007, and rs10211390 for recurrence and rs6590611 for survival in patients with stage II disease; and SNPs rs6124509 and rs11195893 for recurrence in patients with stage III disease. In addition, a significant cumulative effect was observed of multiple risk genotypes and potential gene-gene interactions on recurrence risk.
CONCLUSIONS
To the authors' knowledge, this is the first study to evaluate the association between SNPs within UCEs and clinical outcome in patients with CRC. The results suggested that SNPs within UCEs may be valuable prognostic biomarkers for patients with locally advanced CRC who receive 5-fluorouracil-based chemotherapy.
背景
超保守元件（UCEs）是人类、小鼠和大鼠种系之间完全相同的非编码基因组序列，具有重要的生物学功能。作者假设 UCE 内的单核苷酸多态性（SNPs）与结直肠癌（CRC）患者的临床结局相关。
方法
在 662 例 I 期至 III 期 CRC 患者中，对 48 个 UCE 内的 SNPs 进行了基因分型。在接受氟嘧啶类辅助化疗的 II 期或 III 期 CRC 患者中，使用训练和验证设计分析了基因型与复发和生存之间的关联。训练组包括 115 例 II 期疾病患者和 170 例 III 期疾病患者，验证组包括 88 例 II 期疾病患者和 112 例 III 期疾病患者。
结果
根据疾病分期，有 8 个 SNPs 与临床结局相关。特别是，对于 II 期 CRC 患者，如果至少有 1 个参考 SNP 序列 7849（rs7849）的变异等位基因，在训练组中观察到一致的复发风险增加（风险比[HR]，2.39；95%置信区间[CI]，1.04-5.52），在复制组中（HR，3.70；95%CI，1.42-9.64），在荟萃分析中（HR，2.89；95%CI，1.54-5.41）。其他几个 SNPs 在训练组中是显著的，但在验证组中不是。这些包括 II 期疾病患者的 rs2421099、rs16983007 和 rs10211390 与复发相关，rs6590611 与生存相关；以及 III 期疾病患者的 rs6124509 和 rs11195893 与复发相关。此外，还观察到多个风险基因型和潜在的基因-基因相互作用对复发风险的累积效应。
结论
据作者所知，这是第一项评估 UCE 内 SNPs 与 CRC 患者临床结局之间关系的研究。结果表明，UCE 内的 SNPs 可能是接受 5-氟尿嘧啶类化疗的局部晚期 CRC 患者有价值的预后生物标志物。
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