Pardini Barbara, Bermejo Justo Lorenzo, Naccarati Alessio, Di Gaetano Cornelia, Rosa Fabio, Legrand Carine, Novotny Jan, Vodicka Pavel, Kumar Rajiv
Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mutat Res. 2014 Aug-Sep;766-767:7-13. doi: 10.1016/j.mrfmmm.2014.05.007. Epub 2014 Jun 7.
Treatment with 5-fluorouracil (5-FU) is known to improve survival in many cancers including colorectal cancer. Response to the treatment, overall survival and recurrence show inter-individual variation.
In this study we employed a strategy to search eQTL variants influencing the expression of a large number of genes. We identified four single nucleotide polymorphisms, defined as master regulators of transcription, and genotyped them in a set of 218 colorectal cancer patients undergoing adjuvant 5-FU based therapy.
Our results showed that the minor allele variant of the rs4846126 polymorphism was associated with poor overall and progression-free survival. Patients that were homozygous for the variant allele showed an over two fold increased risk of death (HR 2.20 95%CI 1.05-4.60) and progression (HR 2.88, 95% 1.47-5.63). The integration of external information from publicly available gene expression repositories suggested that the rs4846126 polymorphism deserves further investigation. This variant potentially regulates the gene expression of 273 genes with some of them possibly associated to the patient's response to 5-FU treatment or colorectal cancer.
Present results show that mining of public data repositories in combination with own data can be a fruitful approach to identify markers that affect therapy outcome. In particular, a genetic screen of master regulators may help in order to search for the polymorphisms involved in treatment response in cancer patients.
已知5-氟尿嘧啶（5-FU）治疗可提高包括结直肠癌在内的多种癌症的生存率。对该治疗的反应、总生存期和复发存在个体差异。
在本研究中，我们采用了一种策略来搜索影响大量基因表达的eQTL变异。我们鉴定了四个单核苷酸多态性，将其定义为转录的主要调节因子，并在一组接受基于5-FU辅助治疗的218例结直肠癌患者中对其进行基因分型。
我们的结果表明，rs4846126多态性的次要等位基因变异与较差的总生存期和无进展生存期相关。该变异等位基因纯合的患者死亡风险增加两倍以上（HR 2.20，95%CI 1.05 - 4.60），进展风险增加两倍以上（HR 2.88，95% 1.47 - 5.63）。整合来自公开可用基因表达库的外部信息表明，rs4846126多态性值得进一步研究。该变异可能调节273个基因的表达，其中一些基因可能与患者对5-FU治疗的反应或结直肠癌有关。
目前的结果表明，结合公共数据存储库和自身数据进行挖掘是识别影响治疗结果的标志物的有效方法。特别是，对主要调节因子进行基因筛选可能有助于寻找癌症患者治疗反应中涉及的多态性。
