Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence
Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence
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DOI：
10.1158/1078-0432.ccr-11-1180
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发表时间：
2011-11-01
影响因子：
11.5
通讯作者：
Lenz, Heinz-Josef
中科院分区：
文献类型：
--
作者：
Gerger, Armin;Zhang, Wu;Lenz, Heinz-Josef
目的：最近的证据表明，肿瘤干细胞(CSC)是结肠癌进展和复发的关键因素。CSC基因的胚系变异可能导致基因功能和/或活性的改变，从而导致患者肿瘤复发能力和化疗耐药性的个体差异。我们研究了一组CSC基因的种系多态，以预测III期和高危II期结肠癌患者的肿瘤复发时间(TTR)。实验设计：共有234名在南加州大学接受5-氟尿嘧啶化疗的患者参加了这项研究。结果：CD44rs8193C&gT、alcam rs1157G&gT；和LGR5rs17109924T&gT；C等位基因与TTR值显著相关(9.4年vs.5.4年；HR，0.51；95%CI：0.35-0.93；P=0.022；在按种族分层的多因素分析中，仍有统计学意义。在递归分区中，包括LGR5rs17109924、CD44rs8193和ALDH1A1rs1342024的特定基因变异谱代表了一个高危亚组，其中位TTR值为1.7年(HR，6.71，95%CI：2.71-16.63，P<；0.001)。结论：这是首次发现结肠癌CSC基因中常见的生殖系变异是III期和高危II期结肠癌患者的独立预后标志。临床癌症资源；17(21)；6934-43。(C)2011年AACR。
Purpose: Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patient's tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer.Experimental Design: A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for germline polymorphisms in genes that have been previously associated with colon CSC (CD44, Prominin-1, DPP4, EpCAM, ALCAM, Msi-1, ITGB1, CD24, LGR5, and ALDH1A1) by PCR-RFLP or direct DNA-sequencing.Results: The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001).Conclusion: This is the first study identifying common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients. Clin Cancer Res; 17(21); 6934-43. (C)2011 AACR.