Wheeler Heather E, González-Neira Anna, Pita Guillermo, de la Torre-Montero Julio-Cesar, Alonso Rosario, Lopez-Fernandez Luis A, Alba Emilio, Martín Miguel, Dolan M Eileen
aSection of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA bHuman Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Center cSan Carlos University Hospital dInstitute for Health Research, University Hospital Gregorio Marañón, Madrid eUniversity Hospital Virgen de la Victoria, Malaga, Spain.
Pharmacogenet Genomics. 2014 May;24(5):231-7. doi: 10.1097/FPC.0000000000000037.
A primary challenge in identifying replicable pharmacogenomic markers from clinical genomewide association study (GWAS) trials in oncology is the difficulty in performing a second large clinical trial with the same drugs and dosage regimen. We sought to overcome this challenge by incorporating GWAS results from cell-based studies using the same chemotherapy as a clinical cohort.
In this study, we test whether the overlap between genetic variants identified in a preclinical study and a clinical study on capecitabine is more than expected by chance. A GWAS of capecitabine-induced cytotoxicity was performed in 164 lymphoblastoid cell lines derived from the CEU HapMap population and compared with a GWAS of hand-foot syndrome (HFS), the most frequent capecitabine-induced adverse drug reaction, in Spanish breast and colorectal cancer patients (n=160) treated with capecitabine.
We observed an overlap of 16 single nucleotide polymorphisms associated with capecitabine-induced cytotoxicity (P<0.001) in lymphoblastoid cell lines and HFS (P<0.05) in patients, which is a greater overlap than expected by chance (genotype-phenotype permutation empirical P=0.015). Ten tag single nucleotide polymorphisms, which cover the overlap loci, were genotyped in a second patient cohort (n=85) and one of them, rs9936750, was associated with capecitabine-induced HFS (P=0.0076).
The enrichment results imply that cellular models of capecitabine-induced cytotoxicity may capture components of the underlying polygenic architecture of related toxicities in patients.
在肿瘤学临床全基因组关联研究（GWAS）试验中，识别可重复的药物基因组学标志物面临的一个主要挑战是，难以使用相同药物和给药方案进行第二项大型临床试验。我们试图通过纳入基于细胞研究的GWAS结果来克服这一挑战，这些研究使用与临床队列相同的化疗药物。
在本研究中，我们测试了在一项临床前研究和一项关于卡培他滨的临床研究中鉴定出的基因变异之间的重叠是否超过偶然预期。在来自CEU HapMap人群的164个淋巴母细胞系中进行了卡培他滨诱导的细胞毒性的GWAS，并与西班牙乳腺癌和结直肠癌患者（n = 160）中最常见的卡培他滨诱导的药物不良反应手足综合征（HFS）的GWAS进行比较，这些患者接受了卡培他滨治疗。
我们观察到，在淋巴母细胞系中与卡培他滨诱导的细胞毒性相关的16个单核苷酸多态性（P < 0.001）和患者中的HFS（P < 0.05）存在重叠，这一重叠大于偶然预期（基因型 - 表型置换经验P = 0.015）。在第二个患者队列（n = 85）中对覆盖重叠位点的10个标签单核苷酸多态性进行了基因分型，其中一个rs9936750与卡培他滨诱导的HFS相关（P = 0.0076）。
富集结果表明，卡培他滨诱导的细胞毒性的细胞模型可能捕获了患者中相关毒性潜在多基因结构的组成部分。
