拓扑异构酶I拷贝数改变作为转移性结直肠癌中伊立替康疗效的生物标志物
Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer.
作者信息
Palshof Jesper Andreas, Høgdall Estrid Vilma Solyom, Poulsen Tim Svenstrup, Linnemann Dorte, Jensen Benny Vittrup, Pfeiffer Per, Tarpgaard Line Schmidt, Brünner Nils, Stenvang Jan, Yilmaz Mette, Nielsen Dorte Lisbet
机构信息
Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
出版信息
BMC Cancer. 2017 Jan 11;17(1):48. doi: 10.1186/s12885-016-3001-y.
BACKGROUND
No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients with metastatic colorectal cancer.
METHODS
From a national cohort, we identified 163 patients treated every third week with irinotecan 350 mg/m as second-line therapy. Among these 108 were eligible for analyses and thus entered the study. Primary tumors samples were collected and tissue microarray (TMA) blocks were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses.
RESULTS
In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5-9.5) and 2.00 (range: 0.55-4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82-10.43) and 1.98 (range: 1.22-6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92-2.90) and 2.05 (range: 1.00-6.00), respectively. None of the markers TOP1 CN, TOP1/CEN-20-ratio or TOP1/CEN-2-ratio were associated with progression free survival, overall survival or baseline characteristics. Yet, we observed a borderline association for a stepwise increase of the TOP1 CN in relation to objective response as hazard ratio were 1.35 (95% CI 0.96-1.90; p = 0.081).
CONCLUSIONS
We verified a borderline significant association between increasing TOP1 CN and objective response as previously reported. Applying the probes representing CEN-20 and CEN-2, in order to investigate the ratios of TOP1/CEN-20 and TOP1/CEN-2 provided no further information in search of a biomarker driven patient stratification. Other biomarkers to be paired with TOP1 CN are therefore highly warranted.
背景
目前尚无生物标志物可指导转移性结直肠癌患者化疗的最佳选择。我们检测了拓扑异构酶I（TOP1）的拷贝数以及TOP1/CEN-20和TOP1/CEN-2的比值，作为转移性结直肠癌患者伊立替康疗效的生物标志物。
方法
从一个全国性队列中，我们确定了163例每三周接受350mg/m伊立替康二线治疗的患者。其中108例符合分析条件并进入研究。收集原发性肿瘤样本并制作组织微阵列（TMA）块。使用两种探针混合物进行荧光原位杂交（FISH）分析：TOP1/CEN-20和TOP1/CEN-2。分析仅纳入使用FISH检测到所有三种信号（TOP1、CEN-20和CEN-2）的样本。
结果
在TOP1/CEN-20探针混合物中，TOP1和CEN-20的拷贝数中位数分别为4.46（范围：1.5 - 9.5）和2.00（范围：0.55 - 4.55）。在TOP1/CEN-2探针混合物中，TOP1和CEN-2的拷贝数中位数分别为4.57（范围：1.82 - 10.43）和1.98（范围：1.22 - 6.14）。TOP1/CEN-20比值和TOP1/CEN-2比值的中位数分别为1.25（范围：0.92 - 2.90）和2.05（范围：1.00 - 6.00）。TOP1拷贝数、TOP1/CEN-20比值或TOP1/CEN-2比值均与无进展生存期、总生存期或基线特征无关。然而，我们观察到TOP1拷贝数逐步增加与客观缓解之间存在临界关联，风险比为1.35（95%CI 0.96 - 1.90；p = 0.081）。
结论
正如之前报道的，我们验证了TOP1拷贝数增加与客观缓解之间存在临界显著关联。应用代表CEN-20和CEN-2的探针来研究TOP1/CEN-20和TOP1/CEN-2的比值，在寻找生物标志物驱动的患者分层方面没有提供更多信息。因此，非常有必要寻找与TOP1拷贝数配对的其他生物标志物。
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