Section of Pathobiology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlægevej 88, DK-1870 Frederiksberg, Denmark.
Mol Oncol. 2013 Feb;7(1):101-11. doi: 10.1016/j.molonc.2012.09.001. Epub 2012 Oct 11.
PURPOSE: A Topoisomerase 1 (Top1) poison is frequently included in the treatment regimens for metastatic colorectal cancer (mCRC). However, no predictive biomarkers for Top1 poisons are available. We here report a study on the TOP1 gene copy number in CRC patients and its association with patient prognosis and tumor cell proliferation. EXPERIMENTAL DESIGN: The study included TOP1 and CEN-20 fluorescence in situ hybridization (FISH) analyses on formalin fixed paraffin embedded (FFPE) tissue sections from 154 stage III CRC chemonaïve patients. The frequencies of aberration in the TOP1 gene copy number, the CEN-20 copy number and the TOP1/CEN-20 ratio were analyzed and associated with overall survival (OS), time to recurrence (TTR) and in a subgroup analysis of rectal cancer patients only with time to local recurrence (LR in RC). Moreover, the TOP1 and CEN-20 copy numbers were correlated with the tumor Ki67 proliferation index. RESULTS: 35.7% of the tumors had an increased TOP1 copy number above 4n gene copies per cell and 28.6% and 9.7% had a TOP1/CEN-20 ratio ≥1.5 or ≥2.0, respectively. The TOP1 copy number and the TOP1/CEN-20 ratios were separately added into multivariate analyses as continuous variables, in which also age, gender, primary tumor location and Ki67 status were added as covariates. In contrast to the TOP1/CEN-20 ratio, the TOP1 copy number was significantly associated with OS (HR: 0.62; 95% CI: 0.42-0.90; p = 0.01). Neither the TOP1 copy number nor the ratio was significantly associated with TTR and only the TOP1/CEN-20 ratio was significantly associated with LR in RC (HR: 0.25; 95% CI: 0.08-0.83; p = 0.02). No significant correlation was found between the TOP1 copy number and proliferation, while a weak and inverse correlation between the CEN-20 copy number and proliferation was observed. CONCLUSIONS: This study showed that increased TOP1 gene copy numbers are frequent findings in cancer cells in stage III CRC tumors but unrelated to the proliferative status of the tumors. The association with prognosis is important to consider when planning and analyzing future studies investigating TOP1 as a potential predictive biomarker for Top1 poisons.
目的：拓扑异构酶 1（Top1）抑制剂常用于转移性结直肠癌（mCRC）的治疗方案。然而，目前还没有 Top1 抑制剂的预测性生物标志物。本研究报告了对 CRC 患者 Top1 基因拷贝数的研究及其与患者预后和肿瘤细胞增殖的关系。
实验设计：该研究包括对 154 例 III 期结直肠癌初治患者的福尔马林固定石蜡包埋（FFPE）组织切片进行 Top1 和 CEN-20 荧光原位杂交（FISH）分析。分析 Top1 基因拷贝数、CEN-20 拷贝数和 Top1/CEN-20 比值的异常情况，并与总生存期（OS）、无复发生存期（TTR）相关，在直肠肿瘤患者的亚组分析中还与局部无复发生存期（LR in RC）相关。此外，还分析了 Top1 和 CEN-20 拷贝数与肿瘤 Ki67 增殖指数的相关性。
结果：35.7%的肿瘤存在 Top1 基因拷贝数高于 4n 个细胞/基因拷贝，28.6%和 9.7%的肿瘤分别存在 Top1/CEN-20 比值≥1.5 和≥2.0。Top1 拷贝数和 Top1/CEN-20 比值分别作为连续变量加入多变量分析中，其中还加入了年龄、性别、原发肿瘤位置和 Ki67 状态作为协变量。与 Top1/CEN-20 比值相比，Top1 拷贝数与 OS 显著相关（HR：0.62；95%CI：0.42-0.90；p=0.01）。Top1 拷贝数和比值均与 TTR 无显著相关性，仅 Top1/CEN-20 比值与直肠肿瘤的 LR 显著相关（HR：0.25；95%CI：0.08-0.83；p=0.02）。Top1 拷贝数与增殖无显著相关性，而 CEN-20 拷贝数与增殖呈弱负相关。
结论：本研究表明，III 期 CRC 肿瘤的癌细胞中存在高频的 Top1 基因拷贝数增加，但与肿瘤的增殖状态无关。在计划和分析未来以 Top1 作为 Top1 抑制剂潜在预测性生物标志物的研究时，考虑到与预后的相关性非常重要。
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