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Article Open Access

Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors

  • Authors:
    • Yilan Li
    • Weijie Wang
    • Rong Gao
    • Xueming Xu
    • Yao Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 94
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    Published online on: December 6, 2020
       https://doi.org/10.3892/ol.2020.12355
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Abstract

Tyrosine kinase inhibitors (TKIs) are characterized as multi‑targeted anticancer agents that lack specificity, leading to cardiovascular adverse effects. To date, there are no reliable means to predict the cardiotoxicity of TKIs under development. The present study assessed the usual variants of genes to determine the molecular targets of TKIs associated with heart failure (HF). Gene or gene products affected by TKIs were assessed using the Drug Gene Interaction Database. These genes were investigated in genome‑wide association studies (GWAS) datasets associated with HF at a genome‑wide significant level (P<1x10‑5). Subsequently, single‑nucleotide polymorphisms (SNPs) that reached the established GWAS threshold (P<5x10‑8) were investigated for genome‑wide significance. Based on a threshold score of 3, nine gene loci yielded associations according to their biological function using RegulomeDB. Finally, comprehensive functional analysis of SNPs was performed using bioinformatics databases to identify potential drug targets. Using rSNPBase, rs7115242, rs143160639 and rs870064 were found to interfere with proximal transcription regulation, while rs7115242, rs143160639 and rs117153772 were involved in distal regulation, and most SNPs participated in post‑transcriptional RNA binding protein‑mediated regulation. rs191188930 on platelet‑derived growth factor receptor (PDGFR) α was associated with numerous TKI drugs, including sunitinib, pazopanib, sorafenib, dasatinib and nilotinib. Using RegulomeDB and HaploReg v4.1, rs191188930 was predicted to be located in enhancer histone markers. PhenoScanner GWAS analysis revealed that rs191188930 was associated with other diseases or phenotypes, in addition to HF. Genotype‑Tissue Expression analysis indicated that the PDGFRα gene had the highest median expression in ‘Cells‑Transformed fibroblasts’, and the Search Tool for the Retrieval of Interacting Genes/Proteins revealed the protein‑protein interaction network of PDGFRα. The present findings demonstrated the overlap of TKI‑induced genes and those mediating HF risk, suggesting molecular mechanisms potentially responsible for TKI‑induced HF risk. Additionally, the present genetic study may be helpful to further investigate off‑target drug effects.
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1 

Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, et al: 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines: The task force for cancer treatments and cardiovascular toxicity of the European society of cardiology (ESC). Eur Heart J. 37:2768–2801. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Gyongyosi M, Lukovic D, Zlabinger K, Spannbauer A, Gugerell A, Pavo N, Traxler D, Pils D, Maurer G, Jakab A, et al: Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance. Cardiovasc Res. 116:970–982. 2020.PubMed/NCBI

3 

Gupta SK, Garg A, Bar C, Chatterjee S, Foinquinos A, Milting H, Streckfuß-Bömeke K, Fiedler J and Thum T: Quaking inhibits doxorubicin-mediated cardiotoxicity through regulation of cardiac circular RNA expression. Circ Res. 122:246–254. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Force T, Krause DS and Van Etten RA: Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 7:332–344. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Skubitz KM: Cardiotoxicity monitoring in patients treated with tyrosine kinase inhibitors. Oncologist. 24:e600–e602. 2019. View Article : Google Scholar : PubMed/NCBI

6 

Santoni M, Guerra F, Conti A, Lucarelli A, Rinaldi S, Belvederesi L, Capucci A and Berardi R: Incidence and risk of cardiotoxicity in cancer patients treated with targeted therapies. Cancer Treat Rev. 59:123–131. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Gill D, Georgakis MK, Koskeridis F, Jiang L, Feng Q, Wei WQ, Theodoratou E, Elliott P, Denny JC, Malik R, et al: Use of genetic variants related to antihypertensive drugs to inform on efficacy and side effects. Circulation. 140:270–279. 2019. View Article : Google Scholar : PubMed/NCBI

8 

Griffith M, Griffith OL, Coffman AC, Weible JV, McMichael JF, Spies NC, Koval J, Das I, Callaway MB, Eldred JM, et al: DGIdb: Mining the druggable genome. Nat Methods. 10:1209–1210. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Wagner AH, Coffman AC, Ainscough BJ, Spies NC, Skidmore ZL, Campbell KM, Krysiak K, Pan D, McMichael JF, Eldred JM, et al: DGIdb 2.0: Mining clinically relevant drug-gene interactions. Nucleic Acids Res. 44:D1036–D1044. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Cotto KC, Wagner AH, Feng YY, Kiwala S, Coffman AC, Spies G, Wollam A, Spies NC, Griffith OL and Griffith M: DGIdb 3.0: A redesign and expansion of the drug-gene interaction database. Nucleic Acids Res. 46:D1068–D1073. 2018. View Article : Google Scholar : PubMed/NCBI

11 

Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, Butterworth AS and Staley JR: PhenoScanner V2: An expanded tool for searching human genotype-phenotype associations. Bioinformatics. 35:4851–4853. 2019. View Article : Google Scholar : PubMed/NCBI

12 

Liao X, Lan C, Liao D, Tian J and Huang X: Exploration and detection of potential regulatory variants in refractive error GWAS. Sci Rep. 6:330902016. View Article : Google Scholar : PubMed/NCBI

13 

Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, et al: Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22:1790–1797. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Mesbah-Uddin M, Elango R, Banaganapalli B, Shaik NA and Al-Abbasi FA: In-silico analysis of inflammatory bowel disease (IBD) GWAS loci to novel connections. PLoS One. 10:e01194202015. View Article : Google Scholar : PubMed/NCBI

15 

Wang E, Zhao H, Zhao D, Li L and Du L: Functional prediction of chronic kidney disease susceptibility gene PRKAG2 by comprehensively bioinformatics analysis. Front Genet. 9:5732018. View Article : Google Scholar : PubMed/NCBI

16 

Ward LD and Kellis M: HaploReg v4: Systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 44:D877–D881. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Ward LD and Kellis M: HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40((Database Issue)): D930–D934. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Guo L, Du Y, Chang S, Zhang K and Wang J: rSNPBase: A database for curated regulatory SNPs. Nucleic Acids Res. 42((Database Issue)): D1033–D1039. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Lou J, Gong J, Ke J, Tian J, Zhang Y, Li J, Yang Y, Zhu Y, Gong Y, Li L, et al: A functional polymorphism located at transcription factor binding sites, rs6695837 near LAMC1 gene, confers risk of colorectal cancer in Chinese populations. Carcinogenesis. 38:177–183. 2017.PubMed/NCBI

20 

Ganguly K, Saha T, Saha A, Dutta T, Banerjee S, Sengupta D, Bhattacharya S, Ghosh S and Sengupta M: Meta-analysis and prioritization of human skin pigmentation-associated GWAS-SNPs using ENCODE data-based web-tools. Arch Dermatol Res. 311:163–171. 2019. View Article : Google Scholar : PubMed/NCBI

21 

Casper J, Zweig AS, Villarreal C, Tyner C, Speir ML, Rosenbloom KR, Raney BJ, Lee CM, Lee BT, Karolchik D, et al: The UCSC genome browser database: 2018 update. Nucleic Acids Res. 46:D762–D769. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Haeussler M, Zweig AS, Tyner C, Speir ML, Rosenbloom KR, Raney BJ, Lee CM, Lee BT, Hinrichs AS, Gonzalez JN, et al: The UCSC genome browser database: 2019 update. Nucleic Acids Res. 47:D853–D858. 2019. View Article : Google Scholar : PubMed/NCBI

23 

Lee CM, Barber GP, Casper J, Clawson H, Diekhans M, Gonzalez JN, Hinrichs AS, Lee BT, Nassar LR, Powell CC, et al: UCSC genome browser enters 20th year. Nucleic Acids Res. 48:D756–D761. 2020.PubMed/NCBI

24 

McCall MN, Illei PB and Halushka MK: Complex sources of variation in tissue expression data: Analysis of the GTEx lung transcriptome. Am J Hum Genet. 99:624–635. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Carithers LJ, Ardlie K, Barcus M, Branton PA, Britton A, Buia SA, Compton CC, DeLuca DS, Peter-Demchok J, Gelfand ET, et al: A novel approach to high-quality postmortem tissue procurement: The GTEx project. Biopreserv Biobank. 13:311–319. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Karolchik D, Barber GP, Casper J, Clawson H, Cline MS, Diekhans M, Dreszer TR, Fujita PA, Guruvadoo L, Haeussler M, et al: The UCSC genome browser database: 2014 update. Nucleic Acids Res. 42:D764–D770. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, et al: STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47:D607–D613. 2019. View Article : Google Scholar : PubMed/NCBI

28 

Tallquist MD and Soriano P: Cell autonomous requirement for PDGFRalpha in populations of cranial and cardiac neural crest cells. Development. 130:507–518. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Hoch RV and Soriano P: Roles of PDGF in animal development. Development. 130:4769–4784. 2003. View Article : Google Scholar : PubMed/NCBI

30 

Hong SP, Song S, Cho SW, Lee S, Koh BI, Bae H, Kim KH, Park JS, Do HS, Im I, et al: Generation of PDGFRα+ cardioblasts from pluripotent stem cells. Sci Rep. 7:418402017. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Li Y, Wang W, Gao R, Xu X and Zhang Y: Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors. Oncol Lett 21: 94, 2021.
APA
Li, Y., Wang, W., Gao, R., Xu, X., & Zhang, Y. (2021). Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors. Oncology Letters, 21, 94. https://doi.org/10.3892/ol.2020.12355
MLA
Li, Y., Wang, W., Gao, R., Xu, X., Zhang, Y."Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors". Oncology Letters 21.2 (2021): 94.
Chicago
Li, Y., Wang, W., Gao, R., Xu, X., Zhang, Y."Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors". Oncology Letters 21, no. 2 (2021): 94. https://doi.org/10.3892/ol.2020.12355
Copy and paste a formatted citation
x
Spandidos Publications style
Li Y, Wang W, Gao R, Xu X and Zhang Y: Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors. Oncol Lett 21: 94, 2021.
APA
Li, Y., Wang, W., Gao, R., Xu, X., & Zhang, Y. (2021). Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors. Oncology Letters, 21, 94. https://doi.org/10.3892/ol.2020.12355
MLA
Li, Y., Wang, W., Gao, R., Xu, X., Zhang, Y."Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors". Oncology Letters 21.2 (2021): 94.
Chicago
Li, Y., Wang, W., Gao, R., Xu, X., Zhang, Y."Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors". Oncology Letters 21, no. 2 (2021): 94. https://doi.org/10.3892/ol.2020.12355
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