Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
J Thorac Oncol. 2011 Jan;6(1):132-8. doi: 10.1097/JTO.0b013e318200f415.
Our goal was to identify candidate polymorphisms that could influence overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with carboplatin (CBDCA) and paclitaxel (PTX).
Chemotherapy-naïve stage IIIB or IV NSCLC patients treated with CBDCA (area under the curve = 6 mg/mL/min) and PTX (200 mg/m, 3-hour period) were eligible for this study. The DNA samples were extracted from peripheral blood mononuclear cells before treatment, and genotypes at approximately 110,000 gene-centric single-nucleotide polymorphisms (SNPs) were obtained by Illumina's Sentrix Human-1 Genotyping BeadChip. Statistical analyses were performed by the log-rank test and Cox proportional hazards model.
From July 2002 to May 2004, 105 patients received a total of 308 cycles of treatment. The median survival time (MST) of 105 patients was 17.1 months. In the genome-wide association study, three SNPs were associated significantly with shortened OS after multiple comparison adjustment: rs1656402 in the EIF4E2 gene (MST was 18.0 and 7.7 months for AG [n = 50] + AA [n = 40] and GG [n = 15], respectively; p = 8.4 × 10), rs1209950 in the ETS2 gene (MST = 17.7 and 7.4 months for CC [n = 94] and CT [n = 11] + TT [n = 0]; p = 2.8 × 10), and rs9981861 in the DSCAM gene (MST = 17.1 and 3.8 months for AA [n = 75] + AG [n = 26] and GG [n = 4]; p = 3.5 × 10).
Three SNPs were identified as new prognostic biomarker candidates for advanced NSCLC treated with CBDCA and PTX. The agnostic genome-wide association study may unveil unexplored molecular pathways associated with the drug response, but our findings should be replicated by other investigators.
我们的目标是确定候选多态性，这些多态性可能影响接受卡铂（CBDCA）和紫杉醇（PTX）治疗的晚期非小细胞肺癌（NSCLC）患者的总生存期（OS）。
本研究纳入了接受 CBDCA（曲线下面积=6mg/mL/min）和 PTX（200mg/m，3 小时周期）治疗的化疗初治 IIIB 或 IV 期 NSCLC 患者。在治疗前从外周血单核细胞中提取 DNA 样本，并通过 Illumina 的 Sentrix Human-1 Genotyping BeadChip 获得大约 110,000 个基因中心单核苷酸多态性（SNP）的基因型。通过对数秩检验和 Cox 比例风险模型进行统计分析。
从 2002 年 7 月至 2004 年 5 月，105 例患者共接受了 308 个周期的治疗。105 例患者的中位生存时间（MST）为 17.1 个月。在全基因组关联研究中，在经过多次比较调整后，有三个 SNP 与缩短 OS 显著相关：EIF4E2 基因中的 rs1656402（AG[ n=50] + AA[ n=40]和 GG[ n=15]的 MST 分别为 18.0 和 7.7 个月；p=8.4×10），ETS2 基因中的 rs1209950（CC[ n=94]和 CT[ n=11] + TT[ n=0]的 MST=17.7 和 7.4 个月；p=2.8×10），以及 DSCAM 基因中的 rs9981861（AA[ n=75] + AG[ n=26]和 GG[ n=4]的 MST=17.1 和 3.8 个月；p=3.5×10）。
鉴定了三个新的候选 SNP 作为接受 CBDCA 和 PTX 治疗的晚期 NSCLC 的预后生物标志物。无偏倚的全基因组关联研究可能揭示与药物反应相关的未被探索的分子途径，但我们的发现需要其他研究人员进行复制。
