PDF(Pubmed)
Abstract：
BACKGROUND: Therapy with anti-cancer drugs remain the cornerstone of treating cancer. The effectiveness and safety of anti-cancer drugs vary significantly among individuals due to genetic factors influencing the drug response and metabolism. Data on the pharmacogenomic variations in Sri Lankans related to anti-cancer therapy is sparse. As current treatment guidelines in Sri Lanka often do not consider local pharmacogenomic variants, this study aimed to explore the diversity of pharmacogenomic variants in the Sri Lankan population to pave the way for personalized treatment approaches and improve patient outcomes.
METHODS: Pharmacogenomic data regarding variant-drug pairs of genes CYP2D6, DPYD, NUDT15, EPAS1, and XRCC1 with clinical annotations labelled as evidence levels 1A-2B were obtained from the Pharmacogenomics Knowledgebase database. Their frequencies in Sri Lankans were obtained from an anonymized database that was derived from 541 Sri Lankans who underwent exome sequencing at the Human Genetics Unit, Faculty of Medicine, University of Colombo. Variations in DPYD, NUDT15, and EPAS1 genes are related to increased toxicity to fluoropyrimidines, mercaptopurines, and sorafenib respectively. Variations in CYP2D6 and XRCC1 genes are related to changes in efficacy of tamoxifen and platinum compounds, respectively. Minor allele frequencies of these variants were calculated and compared with other populations.
RESULTS: MAFs of rs1065852 c.100 C > T (CYP2D6), rs3918290 c.1905 + 1G > A (DPYD), rs56038477 c.1236G > A (DPYD), rs7557402 c.1035-7 C > G (EPAS1), rs116855232 c.415 C > T (NUDT15*3), and rs25487 c.1196 A > G (XRCC1) were: 12.9% [95%CI:10.9-14.9], 1.5% [95%CI:0.8-2.2], 1.2% [95%CI:0.5-1.8], 37.7% [95%CI:34.8-40.6], 8.3% [95%CI:6.7-10.0], and 64.0% [95%CI:61.1-66.8], respectively. Frequencies of rs1065852 c.100 C > T (CYP2D6), rs7557402 c.1035-7 C > G (EPAS1), and rs25487 (XRCC1) were significantly lower in Sri Lankans, while frequencies of rs116855232 c.415 C > T (NUDT15*3) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations.
CONCLUSIONS: Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.
METHODS: Pharmacogenomic data regarding variant-drug pairs of genes CYP2D6, DPYD, NUDT15, EPAS1, and XRCC1 with clinical annotations labelled as evidence levels 1A-2B were obtained from the Pharmacogenomics Knowledgebase database. Their frequencies in Sri Lankans were obtained from an anonymized database that was derived from 541 Sri Lankans who underwent exome sequencing at the Human Genetics Unit, Faculty of Medicine, University of Colombo. Variations in DPYD, NUDT15, and EPAS1 genes are related to increased toxicity to fluoropyrimidines, mercaptopurines, and sorafenib respectively. Variations in CYP2D6 and XRCC1 genes are related to changes in efficacy of tamoxifen and platinum compounds, respectively. Minor allele frequencies of these variants were calculated and compared with other populations.
RESULTS: MAFs of rs1065852 c.100 C > T (CYP2D6), rs3918290 c.1905 + 1G > A (DPYD), rs56038477 c.1236G > A (DPYD), rs7557402 c.1035-7 C > G (EPAS1), rs116855232 c.415 C > T (NUDT15*3), and rs25487 c.1196 A > G (XRCC1) were: 12.9% [95%CI:10.9-14.9], 1.5% [95%CI:0.8-2.2], 1.2% [95%CI:0.5-1.8], 37.7% [95%CI:34.8-40.6], 8.3% [95%CI:6.7-10.0], and 64.0% [95%CI:61.1-66.8], respectively. Frequencies of rs1065852 c.100 C > T (CYP2D6), rs7557402 c.1035-7 C > G (EPAS1), and rs25487 (XRCC1) were significantly lower in Sri Lankans, while frequencies of rs116855232 c.415 C > T (NUDT15*3) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations.
CONCLUSIONS: Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.
摘要：
背景：抗癌药物治疗仍然是治疗癌症的基石。由于影响药物反应和代谢的遗传因素，抗癌药物的有效性和安全性在个体之间存在显着差异。与抗癌治疗相关的斯里兰卡人的药物基因组变异数据很少。由于斯里兰卡目前的治疗指南通常不考虑当地的药物基因组变异，本研究旨在探索斯里兰卡人群中药物基因组变异的多样性,为个性化治疗方法铺平道路,并改善患者预后.
方法：关于基因CYP2D6，DPYD，具有标记为证据水平1A-2B的临床注释的NUDT15、EPAS1和XRCC1从药物基因组学知识库数据库获得。他们在斯里兰卡的频率是从一个匿名数据库中获得的，该数据库来自541名在人类遗传学部门接受外显子组测序的斯里兰卡人，医学院,科伦坡大学。DPYD的变化，NUDT15和EPAS1基因与氟嘧啶的毒性增加有关，巯基嘌呤,和索拉非尼分别。CYP2D6和XRCC1基因的变异与他莫昔芬和铂化合物的功效变化有关，分别。计算这些变体的次要等位基因频率并与其他群体进行比较。
结果：rs1065852c.100C>T（CYP2D6）的MAFs，rs3918290c.1905+1G>A(DPYD)，rs56038477c.1236G>A（DPYD），rs7557402c.1035-7C>G（EPAS1），rs116855232c.415C>T(NUDT15*3)，rs25487c.1196A>G（XRCC1）为：12.9%[95CI：10.9-14.9]，1.5%[95CI：0.8-2.2]，1.2%[95CI：0.5-1.8]，37.7%[95CI：34.8-40.6]，8.3%[95CI：6.7-10.0]，和64.0%[95CI：61.1-66.8]，分别。rs1065852c.100C>T(CYP2D6)的频率，rs7557402c.1035-7C>G（EPAS1），rs25487（XRCC1）在斯里兰卡明显较低，与某些西方和亚洲人群相比，斯里兰卡人的rs116855232c.415C>T（NUDT15*3）和rs56038477c.1236G>A（DPYD）的频率明显更高。
结论：与索拉非尼（rs7557402c.84,131C>G）和，氟嘧啶（rs56038477c.1236G>A）和巯基嘌呤（rs116855232c.415C>T）的毒性风险更高，三苯氧胺（rs1065852c.100C>T）和铂化合物（rs25487）的有效性降低。这些发现强调了这些遗传变异对斯里兰卡人抗癌剂量需求的个体差异的潜在贡献。
方法：关于基因CYP2D6，DPYD，具有标记为证据水平1A-2B的临床注释的NUDT15、EPAS1和XRCC1从药物基因组学知识库数据库获得。他们在斯里兰卡的频率是从一个匿名数据库中获得的，该数据库来自541名在人类遗传学部门接受外显子组测序的斯里兰卡人，医学院,科伦坡大学。DPYD的变化，NUDT15和EPAS1基因与氟嘧啶的毒性增加有关，巯基嘌呤,和索拉非尼分别。CYP2D6和XRCC1基因的变异与他莫昔芬和铂化合物的功效变化有关，分别。计算这些变体的次要等位基因频率并与其他群体进行比较。
结果：rs1065852c.100C>T（CYP2D6）的MAFs，rs3918290c.1905+1G>A(DPYD)，rs56038477c.1236G>A（DPYD），rs7557402c.1035-7C>G（EPAS1），rs116855232c.415C>T(NUDT15*3)，rs25487c.1196A>G（XRCC1）为：12.9%[95CI：10.9-14.9]，1.5%[95CI：0.8-2.2]，1.2%[95CI：0.5-1.8]，37.7%[95CI：34.8-40.6]，8.3%[95CI：6.7-10.0]，和64.0%[95CI：61.1-66.8]，分别。rs1065852c.100C>T(CYP2D6)的频率，rs7557402c.1035-7C>G（EPAS1），rs25487（XRCC1）在斯里兰卡明显较低，与某些西方和亚洲人群相比，斯里兰卡人的rs116855232c.415C>T（NUDT15*3）和rs56038477c.1236G>A（DPYD）的频率明显更高。
结论：与索拉非尼（rs7557402c.84,131C>G）和，氟嘧啶（rs56038477c.1236G>A）和巯基嘌呤（rs116855232c.415C>T）的毒性风险更高，三苯氧胺（rs1065852c.100C>T）和铂化合物（rs25487）的有效性降低。这些发现强调了这些遗传变异对斯里兰卡人抗癌剂量需求的个体差异的潜在贡献。
