Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.
University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom.
BMC Med Genomics. 2024 May 24;17(1):143. doi: 10.1186/s12920-024-01919-2.
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.
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.
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 (NUDT153), 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 (NUDT153) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations.
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.
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，抗癌药物在个体中的有效性和安全性差异很大。关于与抗癌治疗相关的斯里兰卡人的药物基因组学变异的数据很少。由于目前斯里兰卡的治疗指南通常不考虑当地的药物基因组学变异，因此本研究旨在探索斯里兰卡人群中药物基因组学变异的多样性，为个性化治疗方法铺平道路，提高患者的治疗效果。
从 Pharmacogenomics Knowledgebase 数据库中获取有关 CYP2D6、DPYD、NUDT15、EPAS1 和 XRCC1 基因的变异-药物对的药物基因组学数据，这些基因的临床注释标记为证据水平 1A-2B。从在科伦坡大学医学院人类遗传学系接受外显子组测序的 541 名斯里兰卡人中获得这些基因在斯里兰卡人中的频率。DPYD、NUDT15 和 EPAS1 基因的变异与氟尿嘧啶类药物、巯嘌呤类药物和索拉非尼的毒性增加有关。CYP2D6 和 XRCC1 基因的变异与他莫昔芬和铂类化合物的疗效变化有关。计算这些变异的次要等位基因频率，并与其他人群进行比较。
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 (NUDT153) 和 rs25487 c.1196 A > G (XRCC1) 的 MAFs 分别为：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]和 64.0%[95%CI:61.1-66.8]。rs1065852 c.100 C > T (CYP2D6)、rs7557402 c.1035-7 C > G (EPAS1) 和 rs25487 (XRCC1) 的频率在斯里兰卡人中显著较低，而 rs116855232 c.415 C > T (NUDT153) 和 rs56038477 c.1236G > A (DPYD) 的频率在斯里兰卡人中显著较高与一些西方和亚洲人群相比。
与索拉非尼（rs7557402 c.84,131 C > G）相比，斯里兰卡人可能具有较低的索拉非尼毒性风险，而与氟尿嘧啶类药物（rs56038477 c.1236G > A）和巯嘌呤类药物（rs116855232 c.415 C > T）相比，斯里兰卡人具有更高的毒性风险，与他莫昔芬（rs1065852 c.100 C > T）和铂类化合物（rs25487）相比，斯里兰卡人的治疗效果降低。这些发现强调了这些遗传变异在个体对斯里兰卡人抗癌药物剂量需求的个体差异中的潜在作用。
