Jeung Hei Cheul, Rha Sun Young, Park Chan Hee, Im Chong-Kun, Shin Sang Joon, Ahn Joong Bae, Noh Sung Hoon, Roh Jae Kyung, Chung Hyun Cheol
Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-Ku, Seoul 120-752, Korea.
Int J Oncol. 2009 Mar;34(3):787-96. doi: 10.3892/ijo_00000204.
Anemia is a unique side effect in Korean gastric cancer patients after S-1 monotherapy. We studied gastric cancer patients from a phase II trial of S-1 monotherapy with a 2-week treatment and 1-week rest schedule. Patients from a phase II trial of S-1 monotherapy with a 4-week treatment and 2-week rest were used as a reference group. The patients were categorized into two groups based on the degree of hemoglobin reduction per cycle of S-1: the mild reduction group (MRG DeltaHb/cycle < or =1.0) or severe reduction group (SRG DeltaHb/cycle >1.0). DeltaHb/cycle was calculated from maximum reduction of hemoglobin per one cycle of the treatment. Microarray-CGH was performed using a 17K cDNA microarray containing 15,723 unique genes. We selected genes with copy number variation defined as amplification (log2R/G >0.68) or deletion (log2R/G <-0.68), and a genetic aberration frequency difference of > or =30% between the MRG and the SRG. There were no differences in clinical factors, S-1 treatment-related factors (dose, dose intensity), toxicity, S-1 metabolism-related gene copy numbers (CYP2A6, DPD), or progression-free survival between the MRG and the SRG. Three genes were selected from microarray-CGH and logistic regression model: logit LN(Z) = (1.321) + (1.038 x PTX1) + (0.211 x MYO5A) + (0.516 x ZNF664). In the SRG, all 3 genes showed a trend of higher copy numbers than the MRG. There were no common anemia-related genes identified from different chemotherapy schedule of S-1 monotherapy. The logistics obtained from 3 genes predicted the hemoglobin reduction with an accuracy of 78%. The AUC was 0.744 for the final regression model. The combined copy number changes of the 3 genes can be developed into a biomarker in predicting S-1 treatment-related anemia.
贫血是韩国胃癌患者接受S-1单药治疗后的一种独特副作用。我们研究了来自一项S-1单药治疗II期试验的胃癌患者，该试验采用2周治疗、1周休息的方案。来自一项采用4周治疗、2周休息的S-1单药治疗II期试验的患者作为参照组。根据S-1每个周期血红蛋白降低程度将患者分为两组：轻度降低组（MRG，ΔHb/周期≤1.0）或重度降低组（SRG，ΔHb/周期>1.0）。ΔHb/周期通过治疗的一个周期内血红蛋白的最大降低值计算得出。使用包含15,723个独特基因的17K cDNA微阵列进行微阵列比较基因组杂交（Microarray-CGH）。我们选择了拷贝数变异的基因，定义为扩增（log2R/G>0.68）或缺失（log2R/G<-0.68），且MRG和SRG之间遗传畸变频率差异≥30%。MRG和SRG在临床因素、S-1治疗相关因素（剂量、剂量强度）、毒性、S-1代谢相关基因拷贝数（CYP2A6、DPD）或无进展生存期方面没有差异。从微阵列-CGH和逻辑回归模型中选择了三个基因：logit LN(Z) = (1.321) + (1.038×PTX1) + (0.211×MYO5A) + (0.516×ZNF664)。在SRG中，所有这三个基因的拷贝数均呈现出高于MRG的趋势。在S-1单药治疗的不同化疗方案中未鉴定出共同的贫血相关基因。由这三个基因得出的逻辑回归预测血红蛋白降低的准确率为78%。最终回归模型的曲线下面积（AUC）为0.744。这三个基因的联合拷贝数变化可开发成为预测S-1治疗相关贫血的生物标志物。
