Frequency of Pharmacogenomic Variants Affecting Efficacy and Safety of Anti-cancer Drugs in a South Asian Population from Sri Lanka

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2024 May 24

PMID 38789983

Authors

Priyanga Ranasinghe

Nirmala Sirisena

Thuwaragesh Vishnukanthan

J N Ariadurai

Sathsarani Thilakarathne

C D Nelanka Priyadarshani

D P Bhagya Hendalage

Vajira H W Dissanayake

Affiliations

Soon will be listed here.

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.

Conclusion: 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.

References

Khaeso K, Udayachalerm S, Komvilaisak P, Chainansamit S, Suwannaying K, Laoaroon N . Meta-Analysis of Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations. Front Pharmacol. 2021; 12:784712. PMC: 8675242. DOI: 10.3389/fphar.2021.784712. View

Zhu X, Wang X, Chao K, Zhi M, Zheng H, Ruan H . NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn's disease. Aliment Pharmacol Ther. 2016; 44(9):967-975. DOI: 10.1111/apt.13796. View

Ranasinghe P, Sirisena N, Senadeera V, Anandagoda G, Dissanayake V . Diversity of pharmacogenomic variants affecting warfarin metabolism in Sri Lankans. Pharmacogenomics. 2022; 23(17):917-923. DOI: 10.2217/pgs-2022-0026. View

Relling M, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui C, Stein C . Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2018; 105(5):1095-1105. PMC: 6576267. DOI: 10.1002/cpt.1304. View

Zhang N, Ouyang Y, Chang J, Liu P, Tian X, Yu J . Pharmacogenetic Association between Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis. Biomed Res Int. 2020; 2020:3520764. PMC: 7603545. DOI: 10.1155/2020/3520764. View

Bukowski K, Kciuk M, Kontek R . Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int J Mol Sci. 2020; 21(9). PMC: 7247559. DOI: 10.3390/ijms21093233. View

Beverage J, Sissung T, Sion A, Danesi R, Figg W . CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci. 2007; 96(9):2224-31. DOI: 10.1002/jps.20892. View

Meulendijks D, Henricks L, Sonke G, Deenen M, Froehlich T, Amstutz U . Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015; 16(16):1639-50. DOI: 10.1016/S1470-2045(15)00286-7. View

Zhou S, Di Y, Chan E, Du Y, Chow V, Xue C . Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab. 2008; 9(8):738-84. DOI: 10.2174/138920008786049302. View

10.

Naushad S, Hussain T, Alrokayan S, Kutala V . Pharmacogenetic profiling of dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population. J Gene Med. 2020; 23(1):e3289. DOI: 10.1002/jgm.3289. View

11.

Lunenburg C, van der Wouden C, Nijenhuis M, Crommentuijn-van Rhenen M, de Boer-Veger N, Buunk A . Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet. 2019; 28(4):508-517. PMC: 7080718. DOI: 10.1038/s41431-019-0540-0. View

12.

Yang R, Niepel M, Mitchison T, Sorger P . Dissecting variability in responses to cancer chemotherapy through systems pharmacology. Clin Pharmacol Ther. 2010; 88(1):34-8. PMC: 2941986. DOI: 10.1038/clpt.2010.96. View

13.

Ranadeva N, Sirisena N, Wetthasinghe T, Noordeen N, Dissanayake V . Design and implementation of a novel pharmacogenetic assay for the identification of the CYP2D6*10 genetic variant. BMC Res Notes. 2022; 15(1):104. PMC: 8925205. DOI: 10.1186/s13104-022-05993-6. View

14.

Chan S, Samaranayake N, Ross C, Toh M, Carleton B, Hayden M . Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics. Pharmacogenet Genomics. 2015; 26(1):28-39. PMC: 4890825. DOI: 10.1097/FPC.0000000000000182. View

15.

Ranasinghe P, Sirisena N, Ariadurai J, Vishnukanthan T, Thilakarathne S, Anandagoda G . Pharmacogenomic variants affecting efficacy and toxicity of statins in a south Asian population from Sri Lanka. Pharmacogenomics. 2023; 24(15):809-819. DOI: 10.2217/pgs-2023-0149. View

16.

Yang S, Hong M, Baek J, Choi H, Zhao W, Jung Y . A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014; 46(9):1017-20. PMC: 4999337. DOI: 10.1038/ng.3060. View

17.

Bai Y, Wu H, Zhang Y . Effects of CYP2D6*10 polymorphism on tamoxifen pharmacokinetics in patients with breast cancer in Asia: a meta-analysis. Cancer Chemother Pharmacol. 2018; 83(1):71-79. DOI: 10.1007/s00280-018-3703-8. View

18.

Kakuta Y, Naito T, Onodera M, Kuroha M, Kimura T, Shiga H . NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. 2015; 16(3):280-5. DOI: 10.1038/tpj.2015.43. View

19.

Froehlich T, Amstutz U, Aebi S, Joerger M, Largiader C . Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity. Int J Cancer. 2014; 136(3):730-9. DOI: 10.1002/ijc.29025. View

20.

Wu H, Xu C, Chen G, Wang J . X-ray repair cross-complementing 1 polymorphism and prognosis of platinum-based chemotherapy in gastric and colorectal cancer: a meta-analysis. J Gastroenterol Hepatol. 2013; 29(5):926-33. DOI: 10.1111/jgh.12444. View