Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Transl Res. 2011 May;157(5):265-72. doi: 10.1016/j.trsl.2011.01.005. Epub 2011 Feb 8.
Identifying patients prior to treatment who are more likely to benefit from chemotherapeutic agents or more likely to experience adverse events is an aim of personalized medicine. Pharmacogenomics offers a potential means of achieving this goal through the discovery of predictive germline genetic biomarkers. When applied particularly to the treatment of head and neck cancers, such information could offer significant benefit to patients as a means of potentially reducing morbidity associated with platinum-based chemotherapy. We developed a genome-wide, cell-based approach to identify single nucleotide polymorphisms (SNPs) associated with platinum susceptibility and then evaluated these SNPs as predictors for response and toxicity in head and neck cancer patients treated with platinum-based therapy as part of a phase II clinical trial. Sixty head and neck cancer patients were evaluated. Of 45 genome-wide SNPs examined, we found that 2 SNPs, rs6870861 (P=0.004; false discovery rate [FDR] <0.05) and rs2551038 (P=0.005; FDR <0.05), were associated significantly with overall response to carboplatin-based induction chemotherapy when incorporated into a model along with total carboplatin exposure. Interestingly, these 2 SNPs are associated strongly with the baseline expression of >20 genes (all P ≤10(-4)), and that 2 genes (SLC22A5 and SLCO4C1) are important organic cation/anion transporters known to affect platinum uptake and clearance. Several other SNPs were associated nominally with carboplatin-related hematologic toxicities. These findings demonstrate importantly that a genome-wide, cell-based model can identify novel germline genetic biomarkers of platinum susceptibility, which are replicable in a clinical setting with treated cancer patients and seem clinically meaningful for potentially enabling future personalization of care in such patients.
在治疗前识别更有可能从化疗药物中获益或更有可能出现不良反应的患者是个性化医学的目标。药物基因组学通过发现预测性种系遗传生物标志物提供了实现这一目标的潜在手段。当特别应用于头颈部癌症的治疗时，此类信息可为患者提供显著益处，有可能降低与铂类化疗相关的发病率。我们开发了一种全基因组、基于细胞的方法来识别与铂类敏感性相关的单核苷酸多态性（SNP），然后评估这些 SNP 作为接受铂类治疗的头颈部癌症患者的反应和毒性预测因子，作为 II 期临床试验的一部分。评估了 60 名头颈部癌症患者。在检查的 45 个全基因组 SNP 中，我们发现 2 个 SNP（rs6870861，P=0.004；错误发现率 [FDR] <0.05 和 rs2551038，P=0.005；FDR <0.05）与总铂暴露一起纳入模型时，与基于卡铂的诱导化疗的总体反应显著相关。有趣的是，这 2 个 SNP 与 >20 个基因的基线表达强烈相关（所有 P ≤10(-4)），并且 2 个基因（SLC22A5 和 SLCO4C1）是重要的有机阳离子/阴离子转运体，已知它们会影响铂类的摄取和清除。其他几个 SNP 与卡铂相关的血液学毒性有显著的关联。这些发现重要地表明，全基因组、基于细胞的模型可以识别新型的铂类敏感性种系遗传生物标志物，这些标志物在接受治疗的癌症患者的临床环境中具有可重复性，并且对于未来在这些患者中实现个性化护理似乎具有临床意义。
