全基因组关联研究非小细胞肺癌患者接受铂类化疗的生存情况。
Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.
机构信息
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1340, Houston, TX 77030, USA.
出版信息
J Natl Cancer Inst. 2011 May 18;103(10):817-25. doi: 10.1093/jnci/djr075. Epub 2011 Apr 11.
BACKGROUND
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).
METHODS
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
RESULTS
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
CONCLUSION
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
背景
个体遗传背景的差异可能会影响晚期非小细胞肺癌（NSCLC）患者对化疗的反应和总生存。
方法
为了确定与这些患者总生存不良相关的遗传变异，我们对在德克萨斯大学 MD 安德森癌症中心接受铂类化疗联合或不联合放疗的 327 例晚期 NSCLC 患者进行了全基因组扫描，共检测了 307260 个单核苷酸多态性（SNP）。在 Mayo 诊所进行了快速验证，随后在西班牙肺癌组 PLATAX 临床试验中对 420 例患者进行了第二次验证。还使用合并 Mayo 诊所和 PLATAX 人群或所有三个人群的合并分析来验证结果。我们通过多变量 Cox 比例风险回归分析评估每个 SNP 与总生存的关联。所有统计检验均为双侧。
结果
在 MD 安德森发现人群中，趋化因子样受体 1（CMKLR1）中的 SNP rs1878022 与总生存不良显著相关（死亡风险比[HR]为 1.59，95%置信区间[CI]为 1.32 至 1.92，P = 1.42×10（-6）），在 PLATAX 临床试验中（HR 为死亡=1.23，95%CI=1.00 至 1.51，P=0.05），在合并的 Mayo 诊所和 PLATAX 验证人群中（HR 为死亡=1.22，95%CI=1.06 至 1.40，P=0.005），在所有三个人群的合并分析中（HR 为死亡=1.33，95%CI=1.19 至 1.48，P=5.13×10（-7））。在合并的 MD 安德森和 Mayo 诊所人群中，携带 rs10937823 的变异基因型与总生存降低相关（死亡风险比[HR]为 1.82，95%置信区间[CI]为 1.42 至 2.33，P=1.73×10（-6）），但在 PLATAX 试验患者人群中并非如此（HR 为死亡=0.96，95%CI=0.69 至 1.35）。
结论
这些结果有可能为未来 NSCLC 患者的个体化化疗治疗提供依据。
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