Stotz Michael, Herzog Sereina A, Pichler Martin, Smolle Maria, Riedl Jakob, Rossmann Christopher, Bezan Angelika, Stöger Herbert, Renner Wilfried, Berghold Andrea, Gerger Armin
Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
Research Unit Genetic Epidemiology and Pharmacogenetics, Division of Clinical Oncology, Medical University of Graz, Graz, Austria.
Anticancer Res. 2017 Apr;37(4):2011-2018. doi: 10.21873/anticanres.11545.
BACKGROUND/AIM: Growing evidence suggests that human cancers are stem cell diseases and recent data support the existence of cancer stem cells (CSCs) in a variety of malignancies, including colon cancer. These CSCs were shown to be capable of initiating tumor development and progression. Several studies have suggested CD133, CD26 and CD44 as markers of tumor-initiating cells of colon cancer. The purpose of the present study was to assess the impact of single-nucleotide polymorphisms (SNPs) in stem cell-related genes on clinical outcome in a large cohort of colon cancer patients with clinical stage II and III.
Data from 599 consecutive patients with colon cancer stage II and III, treated between 1995 and 2011 at a single centre, were retrospectively evaluated. Genomic DNA was extracted from paraffin-embedded normal tissue distant from the tumor to obtain germline DNA. Allelic distribution of polymorphisms was tested for deviation from Hardy-Weinberg equilibrium using χ-test. The association of polymorphisms with time to recurrence (TTR) and overall survival (OS) was analyzed using Kaplan-Meier curves and compared by the log-rank test. Case-wise deletion for missing polymorphisms was used in univariable and multivariable analyses.
CD44 rs187115 showed a statistically significant association with TTR; patients carrying at least one G allele had a significant reduced risk of recurrence compared to patients with the homozygous A/A variant (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.48-0.94, p=0.019). CD44 rs13347 showed a statistically significant association with OS. Patients carrying at least one T allele in rs13347 had a significantly reduced risk of death compared to patients with the homozygous C/C variant (HR=0.61, 95% CI=0.41-0.92, p=0.019). None of the other investigated polymorphisms (CD44 rs187116, CD44 rs7116432, CD44 rs353639, DPP4 rs2268889, DPP4 rs3788979, DPP4 rs7608798 and CD133 rs2240688) were associated with either TTR or OS.
Germline variants rs13347 and rs187115 in the stem cell gene CD44 are prognostically relevant in stage II and III colon cancer patients.
背景/目的：越来越多的证据表明人类癌症是干细胞疾病，最近的数据支持在包括结肠癌在内的多种恶性肿瘤中存在癌症干细胞（CSCs）。这些癌症干细胞被证明能够启动肿瘤的发展和进展。几项研究表明CD133、CD26和CD44是结肠癌肿瘤起始细胞的标志物。本研究的目的是评估干细胞相关基因中的单核苷酸多态性（SNPs）对一大群临床II期和III期结肠癌患者临床结局的影响。
回顾性评估了1995年至2011年在单一中心接受治疗的599例连续的II期和III期结肠癌患者的数据。从距肿瘤较远的石蜡包埋正常组织中提取基因组DNA以获得种系DNA。使用χ检验测试多态性的等位基因分布是否偏离哈迪-温伯格平衡。使用Kaplan-Meier曲线分析多态性与复发时间（TTR）和总生存期（OS）的关联，并通过对数秩检验进行比较。在单变量和多变量分析中使用缺失多态性的逐例删除法。
CD44 rs187115与TTR显示出统计学上的显著关联；与纯合A/A变体患者相比，携带至少一个G等位基因的患者复发风险显著降低（风险比（HR）=0.67，95%置信区间（CI）=0.48-0.94，p=0.019）。CD44 rs13347与OS显示出统计学上的显著关联。与纯合C/C变体患者相比，rs13347中携带至少一个T等位基因的患者死亡风险显著降低（HR=0.61，95%CI=0.41-0.92，p=0.019）。其他研究的多态性（CD44 rs187116、CD44 rs7116432、CD44 rs353639、DPP4 rs2268889、DPP4 rs3788979、DPP4 rs7608798和CD133 rs2240688）均与TTR或OS无关。
干细胞基因CD44中的种系变体rs13347和rs187115在II期和III期结肠癌患者中具有预后相关性。
