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首页> 外文期刊>Pharmacogenomics >Pharmacogenetic analysis in neoadjuvant chemoradiation for rectal cancer: high incidence of somatic mutations and their relation with response.
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Pharmacogenetic analysis in neoadjuvant chemoradiation for rectal cancer: high incidence of somatic mutations and their relation with response.

机译：直肠癌新辅助化学放疗的药物遗传学分析：体细胞突变的高发生率及其与反应的关系。

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AIMS: The identification of predictive markers of response to chemoradiotherapy treatment remains a promising approach for patient management in order to obtain the best response with minor side effects. Initially, we investigated whether the analysis of several markers previously studied and others not yet evaluated could predict response to 5-fluorouracil- and capecitabine-based neoadjuvant treatment in locally advanced rectal cancer. METHODS & MATERIALS: We studied germline and tumoral samples of 65 stage II/III rectal patients. A panel of pharmacogenetic markers was genotyped in paired peripheral blood samples and rectal cancer tumors. RESULTS: Our results seem to confirm the previously described association of thymidylate synthase and the prediction of chemoradiotherapy response in rectal cancer. However, it failed to confirm the clinical utility proposed for XRCC1, ERCC1, ERCC2, MTHFR and EGFR polymorphisms in blood/germline samples. Subsequently, with the aim of improving prediction of individual response and assessing the role of studied polymorphisms in response to treatment, we determined if changes in tumor response to these markers could predict clinical outcome. We found a high degree of changes between germline and tumor samples, mainly somatic mutations without microsatellite instability, and a minor frequency of loss-of-heterozygosity events. In tumoral samples, XRCC1 appeared to be significantly associated (p = 0.006) with downstaging of the tumor (odds ratio: 7.93; 95% CI: 1.03-60.83), but the increasing of TYMS low-expression alleles contradict the previous results observed in germline samples. CONCLUSION: The detection of somatic mutations in rectal cancer tumors led us to re-evaluate the utility of the tests performed in blood samples for these polymorphisms in rectal cancer. Furthermore, studies aimed at assessing the influence of pharmacogenetic markers in treatment response performed in blood samples should take into account the particular pattern of hypermutability present in each tumor type. We hypothesize that different patterns of hypermutability present in each tumor type would be related to the different results in association studies related to response to the treatment.
机译：目的：识别对放化疗治疗反应的预测标志物仍然是一种有前途的方法，可用于患者管理，以便获得最佳的治疗效果并具有较小的副作用。最初，我们调查了先前研究的几种标记物的分析以及尚未评估的其他标记物的分析是否可以预测局部晚期直肠癌对基于5-氟尿嘧啶和卡培他滨的新辅助治疗的反应。方法和材料：我们研究了65名II / III期直肠患者的种系和肿瘤样本。在成对的外周血样品和直肠癌肿瘤中对一组药物遗传学标记进行基因分型。结果：我们的结果似乎证实了胸苷酸合酶与直肠癌放化疗反应预测之间的关联。然而，它未能证实对血液/生殖细胞样品中的XRCC1，ERCC1，ERCC2，MTHFR和EGFR多态性提议的临床实用性。随后，为了改善对个体反应的预测并评估研究的多态性对治疗的作用，我们确定了对这些标志物的肿瘤反应变化是否可以预测临床结果。我们发现种系和肿瘤样品之间的变化很大，主要是体细胞突变，无微卫星不稳定，杂合子丢失事件的发生频率较小。在肿瘤样品中，XRCC1似乎与肿瘤的分期显着相关（p = 0.006）（几率：7.93; 95％CI：1.03-60.83），但是TYMS低表达等位基因的增加与先前观察到的结果相矛盾。种系样品。结论：直肠癌肿瘤中体细胞突变的检测使我们重新评估了血液样本中检测这些基因多态性在直肠癌中的效用。此外，旨在评估药物遗传学标志物对血液样本中治疗反应的影响的研究应考虑每种肿瘤类型中存在的超变异性的特定模式。我们假设每种肿瘤类型中存在的不同类型的超变异性将与与治疗反应相关的关联研究中的不同结果相关。

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