Nygård Sune Boris, Christensen Ib Jarle, Nielsen Signe Lykke, Nielsen Hans Jørgen, Brünner Nils, Spindler Karen-Lise Garm
Section for Molecular Disease Biology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , 49 Strandboulevarden, DK-2100 Copenhagen Ø , Denmark.
Scand J Gastroenterol. 2014 Jan;49(1):84-91. doi: 10.3109/00365521.2013.856464. Epub 2013 Nov 21.
DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer.
Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed by fluorescence in situ hybridization using a technically validated dual-probe combination that hybridizes to TOP1, located at 20q12-q13.1, and to the centromere region of chromosome 20 (CEN-20). In univariate logistic regression models, the TOP1 signal count per cell and the TOP1/CEN-20 ratio were associated with objective response, which was evaluated according to RECIST v.1.1.
Gain of TOP1 was identified in 52.6% and 37.2% using the following cutoff values: TOP1 signal count per cell ≥3.6 and TOP1/CEN-20 ≥1.5, respectively. A borderline significant association (Odds ratio (OR): 1.62; p = 0.07) between a stepwise increase in the TOP1 signal count and objective response was demonstrated. In relation to the applied cutoff values, nonsignificant associations with objective response were identified for the TOP1 signal count (OR: 2.41; p = 0.23) and for the TOP1/CEN-20 ratio (OR: 2.05; p = 0.30).
Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted.
DNA拓扑异构酶I是伊立替康疗效的一种假定生物标志物，此前已在蛋白质水平证明其与临床相关。本研究的目的是首次对转移性结直肠癌患者接受伊立替康治疗后DNA拓扑异构酶I基因（TOP1）拷贝数与客观缓解之间的关联进行临床研究。
纳入78例接受二线伊立替康单药治疗的患者的福尔马林固定、石蜡包埋肿瘤样本。使用经过技术验证的双探针组合通过荧光原位杂交评估TOP1，该双探针组合与位于20q12 - q13.1的TOP1以及20号染色体着丝粒区域（CEN - 20）杂交。在单变量逻辑回归模型中，每个细胞的TOP1信号计数和TOP1/CEN - 20比值与客观缓解相关，客观缓解根据RECIST v.1.1进行评估。
分别使用以下临界值在52.6%和37.2%的样本中鉴定出TOP1扩增：每个细胞的TOP1信号计数≥3.6以及TOP1/CEN - 20≥1.5。TOP1信号计数逐步增加与客观缓解之间显示出临界显著关联（优势比（OR）：1.62；p = 0.07）。就应用的临界值而言，未发现TOP1信号计数（OR：2.41；p = 0.23）和TOP1/CEN - 20比值（OR：2.05；p = 0.30）与客观缓解有显著关联。
尽管本研究存在局限性，但TOP1与客观缓解之间的正相关表明，非常有必要在更大的肿瘤样本中进行进一步分析，最好是在随机环境中。
