Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors

The Pharmacogenomics Journal volume 22, pages 82–88 (2022)Cite this article

Subjects

A Correction to this article was published on 21 December 2021

This article has been updated

Abstract

No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54–9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09–1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors.

ClinicalTrials.gov Identifier:NCT00073307 (TARGET).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: CONSORT and quality control flowchart for the TARGET study.
Fig. 2: Effect of genotypes of rs427554 on bevacizumab-induced hypertension (replication set).
Fig. 3: Proposed model for lower and higher risk of developing hypertension induced by VEGF-pathway inhibitors in patients with the G and A allele of rs444904 and rs427554 (Created with BioRender.com).

Similar content being viewed by others

Change history

References

  1. Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  CAS  Google Scholar 

  2. Nexavar (Sorafenib). 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf. Accessed 28 Jul 2020.

  3. Costa LJ, Drabkin HA. Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies. Oncologist. 2007;12:1404–15.

    Article  CAS  Google Scholar 

  4. Li Y, Li S, Zhu Y, Liang X, Meng H, Chen J, et al. Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis. J Clin Hypertens. 2014;16:177–85.

    Article  CAS  Google Scholar 

  5. Mir O, Coriat R, Cabanes L, Ropert S, Billemont B, Alexandre J, et al. An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity. Oncologist. 2011;16:1325–32.

    Article  CAS  Google Scholar 

  6. Qi WX, Lin F, Sun YJ, Tang LN, He AN, Yao Y, et al. Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis. Cancer Chemother Pharm. 2013;71:431–9.

    Article  CAS  Google Scholar 

  7. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncologica. 2009;48:9–17.

    Article  CAS  Google Scholar 

  8. Maitland ML, Kasza KE, Karrison T, Moshier K, Sit L, Black HR, et al. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res. 2009;15:6250–7.

    Article  CAS  Google Scholar 

  9. Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.

    Article  CAS  Google Scholar 

  10. Horowitz JR, Rivard A, Van Der Zee R, Hariawala M, Sheriff DD, Esakof DD, et al. Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension: evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol. 1997;17:2793–2800.

    Article  CAS  Google Scholar 

  11. Rini BI. Quantifying hypertension in patients with cancer treated with sorafenib. Lancet Oncol. 2008;9:86–87.

    Article  Google Scholar 

  12. Qin C, Cao Q, Li P, Wang S, Wang J, Wang M, et al. The influence of genetic variants of sorafenib on clinical outcomes and toxic effects in patients with advanced renal cell carcinoma. Sci Rep. 2016;6:20089.

    Article  CAS  Google Scholar 

  13. Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD. Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: Mechanisms and potential use as a biomarker. Semin Nephrol. 2010;30:591–601.

    Article  CAS  Google Scholar 

  14. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl J Med. 2007;356:125–34.

    Article  CAS  Google Scholar 

  15. Crona DJ, Skol AD, Leppanen VM, Glubb DM, Etheridge AS, Hilliard E, et al. Genetic variants of VEGFA and FLT4 are determinants of survival in renal cell carcinoma patients treated with sorafenib. Cancer Res. 2019;79:231–41.

    Article  CAS  Google Scholar 

  16. Quintanilha JCF, Wang J, Sibley AB, Jiang C, Etheridge AS, Shen F et al. Bevacizumab-induced hypertension and proteinuria: a genome-wide analysis of more than 1,000 patients. Br J Cancer 2021. https://doi.org/10.1038/s41416-021-01557-w

  17. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: Phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22.

    Article  CAS  Google Scholar 

  18. Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, et al. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016;34:2602–9.

    Article  CAS  Google Scholar 

  19. Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30:1534–40.

    Article  CAS  Google Scholar 

  20. Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, et al. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N0. J Clin Oncol. 2015;33:2361–9.

    Article  CAS  Google Scholar 

  21. Innocenti F, Owzar K, Cox NL, Evans P, Kubo M, Zembutsu H, et al. A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. Clin Cancer Res. 2012;18:577–84.

    Article  CAS  Google Scholar 

  22. Baldwin RM, Owzar K, Zembutsu H, Chhibber A, Kubo M, Jiang C, et al. A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res. 2012;18:5099–109.

    Article  CAS  Google Scholar 

  23. Rashkin SR, Chua KC, Ho C, Mulkey F, Jiang C, Mushiroda T, et al. A pharmacogenetic prediction model of progression-free survival in breast cancer using genome-wide genotyping data from CALGB 40502 (Alliance). Clin Pharm Ther. 2019;105:738–45.

    Article  CAS  Google Scholar 

  24. Machiela MJ, Chanock SJ. LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31:3555–7.

    Article  CAS  Google Scholar 

  25. Zhang W, Gamazon ER, Zhang X, Konkashbaev A, Liu C, Szilágyi KL, et al. SCAN database: facilitating integrative analyses of cytosine modification and expression QTL. Database. 2015;27:bav025.

    Article  Google Scholar 

  26. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22:1790–7.

    Article  CAS  Google Scholar 

  27. Dayem Ullah AZ, Oscanoa J, Wang J, Nagano A, Lemoine NR, Chelala C. SNPnexus: assessing the functional relevance of genetic variation to facilitate the promise of precision medicine. Nucleic Acids Res. 2018;46:W109–W113.

    Article  Google Scholar 

  28. Ardlie KG, DeLuca DS, Segrè AV, Sullivan TJ, Young TR, Gelfand ET, et al. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.

    Article  Google Scholar 

  29. Zuo C, Shin S, Keleş S. AtSNP: Transcription factor binding affinity testing for regulatory SNP detection. Bioinformatics. 2015;31:3353–5.

    Article  CAS  Google Scholar 

  30. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics. Cancer Res. 2000;60:1541–5.

    CAS  PubMed  Google Scholar 

  31. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.

    Article  CAS  Google Scholar 

  32. Tassan N AL, Khalil D, Shinwari J, Sharif L AL, Bavi P, Abduljaleel Z, et al. A Missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia. Hum Mutat. 2012;33:351–4.

    Article  Google Scholar 

  33. Li LY, Kim HJ, Park SA, Lee SH, Kim LK, Lee JY, et al. Genetic profiles associated with chemoresistance in patient-derived xenograft models of ovarian cancer. Cancer Res Treat. 2019;51:1117–27.

    Article  CAS  Google Scholar 

  34. Buniello A, Macarthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47:D1005–D1012.

    Article  CAS  Google Scholar 

  35. Shymanets A, Prajwal, Bucher K, Beer-Hammer S, Harteneck C, Nürnberg B. P87 and p101 subunits are distinct regulators determining class I B phosphoinositide 3-kinase (PI3K) specificity. J Biol Chem. 2013;288:31059–68.

    Article  CAS  Google Scholar 

  36. Serban D, Leng J, Cheresh D. H-ras regulates angiogenesis and vascular permeability by activation of distinct downstream effectors. Circ Res. 2008;102:1350–8.

    Article  CAS  Google Scholar 

  37. Blattler A, Farnham PJ. Cross-talk between site-specific transcription factors and DNA methylation states. J Biol Chem. 2013;288:34287–94.

    Article  CAS  Google Scholar 

  38. Sherry ST. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U24CA196171, R21CA139280-01, and K07CA140390-01. JCFQ was supported by the São Paulo Research Foundation (FAPESP 2018/04491-2).

Author information

Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Julia C. F. Quintanilha, Alessandro Racioppi, Amy S. Etheridge, Stefanie Denning, Daniel J. Crona & Federico Innocenti

  2. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jin Wang & Danyu Lin

  3. Bayer Health Care Pharmaceuticals, Whippany, NJ, USA

    Carol E. Peña

  4. Department of Medicine, The University of Chicago, Chicago, IL, USA

    Andrew D. Skol

  5. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Daniel J. Crona

  6. Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC, USA

    Daniel J. Crona

Authors
  1. Julia C. F. Quintanilha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandro Racioppi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amy S. Etheridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefanie Denning
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carol E. Peña
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrew D. Skol
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel J. Crona
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Danyu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Federico Innocenti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JCFQ contributed to formal analysis, investigation and writing – original draft, review and editing. AR contribute to formal analysis and investigation. JW contributed to data curation, methodology and formal analysis. ASE contributed to formal analysis, investigation and writing – review and editing. SD contributed to formal analysis and investigation. CEP was responsible for resources. ADS contributed to data curation, formal analysis and methodology. DJC contributed to formal analysis and writing – review and editing. DL contributed to data curation, methodology and supervision. FI was responsible for conceptualization and funding acquisition, and contributed to formal analysis, investigation, methodology, supervision and writing – original draft, review and editing.

Corresponding authors

Correspondence to Julia C. F. Quintanilha or Federico Innocenti.

Ethics declarations

Competing interests

JCFQ, JW, DL, and FI are coinventors of a patent application, serial number 16/932,002. FI is an advisor for Emerald Lake Safety. These relationships have been disclosed to and are under management by UNC-Chapel Hill. CEP was employed by Bayer Health Care Pharmaceuticals at the time this work was conceived.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: The Funding Information has been revised.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quintanilha, J.C.F., Racioppi, A., Wang, J. et al. PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors. Pharmacogenomics J 22, 82–88 (2022). https://doi.org/10.1038/s41397-021-00261-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-021-00261-5

Search

Advanced search

Quick links