巴西亚马逊地区胃肠道癌患者中 FPGS、ABCC4、SLC29A1 和 MTHFR 基因对氟嘧啶类药物药物基因组学的影响。
Influence of FPGS, ABCC4, SLC29A1, and MTHFR genes on the pharmacogenomics of fluoropyrimidines in patients with gastrointestinal cancer from the Brazilian Amazon.
机构信息
Núcleo de Pesquisas Em Oncologia, Universidade Federal Do Pará, Belém, Pará, Brazil.
Hospital Ophir Loyola, Belém, Pará, Brazil.
出版信息
Cancer Chemother Pharmacol. 2021 Nov;88(5):837-844. doi: 10.1007/s00280-021-04327-w. Epub 2021 Jul 31.
PURPOSE
Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon.
METHODS
The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs).
RESULTS
The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction.
CONCLUSION
Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.
目的
氟嘧啶类药物是治疗癌症患者最常用的药物之一，尽管它们具有较高的相关毒性。本研究分析了参与氟嘧啶类药物药代动力学的 17 个药物基因中的 33 个多态性，这些基因在巴西亚马逊地区接受氟嘧啶类药物治疗的胃肠道癌症患者中。
方法
研究人群由 216 名患者组成，其中 92 名患者的解剖病理学诊断为胃癌，124 名患者为结直肠癌。使用 TaqMan OpenArray 基因分型技术通过等位基因鉴别对单核苷酸多态性（SNP）进行基因分型，使用 32 个定制的检测试剂盒进行基因分型，在 QuantStudio ™ 12K Flex Real-Time PCR System（Applied Biosystems，Life Technologies，Carlsbad USA）上运行。使用 61 个常染色体祖先信息标记物（AIMs）进行祖先分析。
结果
研究人群的欧洲裔平均值为 48.1%，美洲原住民为 31.1%，非洲裔为 20.8%。在 FPGS 的 rs4451422（p=0.001；OR 3.40；95%CI 1.65-7.00 和 p=0.006；OR 4.63；95%CI 1.56-13.72）和 ABCC4 的 rs9524885（p=0.023；OR 2.74；95%CI 1.14-6.65 和 p=0.024；OR 5.36；IC 95% 1.24-23.11）基因中，发现了一般毒性和严重毒性的显著风险关联。SLC29A1 基因中的 rs760370（p=0.009；OR 6.71；95%CI 1.16-8.21）和 MTHFR 毒性基因中的 rs1801133（p=0.023；OR 3.09；95%CI 1.16-8.21）也显示出显著意义，尽管仅针对严重毒性。本研究中的结果没有进行统计学分析校正。
结论
ABCC4、FPGS、SLC29A1 和 MTHFR 基因中的四个多态性可能是巴西亚马逊地区氟嘧啶类药物治疗精准医学的潜在预测生物标志物，该地区具有独特的遗传背景。
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