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整合基于细胞和临床的全基因组研究，以鉴定导致神经母细胞瘤患者治疗失败的遗传变异。

Integrating cell-based and clinical genome-wide studies to identify genetic variants contributing to treatment failure in neuroblastoma patients.

机构信息

Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Chicago, Chicago, Illinois, USA.

Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.

出版信息

Clin Pharmacol Ther. 2014 Jun;95(6):644-52. doi: 10.1038/clpt.2014.37. Epub 2014 Feb 18.

DOI:10.1038/clpt.2014.37
PMID:24549002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4029857/
Abstract

High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide (4HC; n = 422) and phosphoramide mustard (PM; n = 428). Genome-wide association studies were performed to identify single-nucleotide polymorphisms (SNPs) associated with sensitivity to 4HC and PM. SNPs consistently associated with LCL sensitivity were analyzed for associations with event-free survival (EFS) in patients. Two linked SNPs, rs9908694 and rs1453560, were found to be associated with (i) sensitivity to PM in LCLs across populations and (ii) EFS in all patients (P = 0.01) and within the high-risk subset (P = 0.05). Our study highlights the value of cell-based models to identify candidate variants that may predict response to treatment in patients with cancer.

摘要

高危神经母细胞瘤是一种侵袭性恶性肿瘤，治疗失败率很高。我们评估了与两种环磷酰胺衍生物体外敏感性相关的遗传变异，以关联神经母细胞瘤患者（n = 2,709）的独立复制队列中的临床反应。为了确定敏感性，淋巴母细胞系（LCL）暴露于不同浓度的 4-羟环磷酰胺（4HC；n = 422）和磷酰胺 mustard（PM；n = 428）中。进行全基因组关联研究以确定与 4HC 和 PM 敏感性相关的单核苷酸多态性（SNP）。对与患者无事件生存（EFS）相关的一致与 LCL 敏感性相关的 SNP 进行分析。发现两个连锁 SNP，rs9908694 和 rs1453560，（i）与人群中 LCL 对 PM 的敏感性相关，（ii）与所有患者（P = 0.01）和高危亚组（P = 0.05）的 EFS 相关。我们的研究强调了基于细胞的模型在识别可能预测癌症患者治疗反应的候选变异方面的价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/42e89033102d/nihms566410f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/eee5e92281a3/nihms566410f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/7c25e066c488/nihms566410f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/db000233ccc2/nihms566410f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/42e89033102d/nihms566410f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/eee5e92281a3/nihms566410f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/5626c396f8fa/nihms566410f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/2e7c6835cc7c/nihms566410f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/7c25e066c488/nihms566410f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/db000233ccc2/nihms566410f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c844/4029857/42e89033102d/nihms566410f6.jpg

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