Skip to main content

Advertisement

SpringerLink
Log in

Expression of PBRM1 as a prognostic predictor in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitor

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Objective

PBRM1, located on 3p21, functions as a tumor suppressor and somatic mutation of PBRM1 is frequent in clear cell renal cell carcinoma (ccRCC). This study aims to determine the influence of PBRM1 expression on the prognosis of patients with mRCC receiving tyrosine kinase inhibitor (TKI) treatment.

Methods

We identified 116 mRCC patients who were administered sunitinib or sorafenib as first-line therapy, between January 2006 and December 2016 at our institution. PBRM1 expression was assessed by immunohistochemistry. The Kaplan–Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS), log-rank test was used to compare the survival outcomes between patients with low and high PBRM1 expression levels, and the Cox proportional hazard regression model was used to estimate the prognostic value. Prognostic accuracy was determined using Harrell concordance index, and nomograms were built to evaluate the prognosis of mRCC.

Results

Patients with low PBRM1 expression had significantly shorter median PFS (9 vs 26 months, P < 0.001) and OS (21 vs 44 months, P < 0.001) than those with high expression. Multivariate analysis showed that PBRM1 expression was an independent predictor of PFS (HR 1.975, P = 0.013) and OS (HR 2.282, P = 0.007). The model built by the addition of PBRM1 improved the C-index of PFS and OS to 0.72 and 0.82, respectively.

Conclusions

The expression of PBRM1 could be a significant prognostic factor for mRCC patients treated with targeted therapy, and it increases the prognostic accuracy of the established prognostic model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hsieh JJ, Purdue MP, Signoretti S et al (2017) Renal cell carcinoma. Nat Rev Disease Primers 3:17009. https://doi.org/10.1038/nrdp.2017.9

    Article  PubMed  Google Scholar 

  2. Harshman LC, Xie W, Bjarnason GA et al (2012) Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study. Lancet Oncol 13(9):927–935. https://doi.org/10.1016/s1470-2045(12)70285-1

    Article  CAS  PubMed  Google Scholar 

  3. Ko JJ, Xie W, Kroeger N et al (2015) The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol 16(3):293–300. https://doi.org/10.1016/s1470-2045(14)71222-7

    Article  PubMed  Google Scholar 

  4. Motzer RJ, Bacik J, Murphy BA et al (2002) Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 20(1):289–296. https://doi.org/10.1200/JCO.2002.20.1.289

    Article  CAS  Google Scholar 

  5. Piva F, Santoni M, Matrana MR et al (2015) BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Exp Rev Mol Diagn 15(9):1201–1210. https://doi.org/10.1586/14737159.2015.1068122

    Article  CAS  Google Scholar 

  6. Brugarolas J (2014) Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 32(18):1968–1976. https://doi.org/10.1200/JCO.2012.45.2003

    Article  CAS  Google Scholar 

  7. Cancer Genome Atlas Research N (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499(7456):43–49. https://doi.org/10.1038/nature12222

    Article  CAS  Google Scholar 

  8. Hogner A, Krause H, Jandrig B et al (2018) PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient's overall survival. Urol Oncol 36(3):94e91–94e14. https://doi.org/10.1016/j.urolonc.2017.10.027

    Article  CAS  Google Scholar 

  9. Manley BJ, Reznik E, Ghanaat M et al (2019) Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations. Urol Oncol 37(1):12–17. https://doi.org/10.1016/j.urolonc.2017.10.012

    Article  PubMed  Google Scholar 

  10. Park JS, Lee HJ, Cho NH et al (2019) Risk prediction tool for aggressive tumors in clinical T1 stage clear cell renal cell carcinoma using molecular biomarkers. Comput Struct Biotechnol J 17:371–377. https://doi.org/10.1016/j.csbj.2019.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hsieh JJ, Chen D, Wang PI et al (2017) Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol 71(3):405–414. https://doi.org/10.1016/j.eururo.2016.10.007

    Article  CAS  PubMed  Google Scholar 

  12. Powles T, Albiges L, Staehler M et al (2017) Updated European Association of Urology guidelines recommendations for the treatment of first-line metastatic clear cell renal cancer. Eur Urol. https://doi.org/10.1016/j.eururo.2017.11.016

    Article  PubMed  Google Scholar 

  13. Miao D, Margolis CA, Gao W et al (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359(6377):801–806. https://doi.org/10.1126/science.aan5951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kakarougkas A, Ismail A, Chambers AL et al (2014) Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol Cell 55(5):723–732. https://doi.org/10.1016/j.molcel.2014.06.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim SH, Park WS, Park EY et al (2017) The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: a retrospective study of tissue microarrays using immunohistochemistry. PLoS ONE 12(6):e0179610. https://doi.org/10.1371/journal.pone.0179610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. da Costa WH, da Cunha IW, Fares AF et al (2018) Prognostic impact of concomitant loss of PBRM1 and BAP1 protein expression in early stages of clear cell renal cell carcinoma. Urol Oncol 36(5):243e241–243e248. https://doi.org/10.1016/j.urolonc.2018.01.002

    Article  CAS  Google Scholar 

  17. Wang Z, Peng S, Guo L et al (2018) Prognostic and clinicopathological value of PBRM1 expression in renal cell carcinoma. Clin Chim Acta Int J Clin Chem 486:9–17. https://doi.org/10.1016/j.cca.2018.07.014

    Article  CAS  Google Scholar 

  18. Kapur P, Peña-Llopis S, Christie A et al (2013) Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 14(2):159–167. https://doi.org/10.1016/s1470-2045(12)70584-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cai W, Kong W, Dong B et al (2017) Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first-line therapy for Chinese patients with metastatic renal cell carcinoma. Chin J Cancer 36(1):64. https://doi.org/10.1186/s40880-017-0230-7

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ye DW, Zhang HL (2014) Critical appraisal of sorafenib in the treatment of Chinese patients with renal cell carcinoma. OncoTargets Ther 7:925–935. https://doi.org/10.2147/OTT.S41828

    Article  CAS  Google Scholar 

  21. Zhang GM, Zhu Y, Gu WJ et al (2016) Pretreatment neutrophil-to-lymphocyte ratio predicts prognosis in patients with metastatic renal cell carcinoma receiving targeted therapy. Int J Clin Oncol 21(2):373–378. https://doi.org/10.1007/s10147-015-0894-4

    Article  CAS  PubMed  Google Scholar 

  22. Takamatsu K, Mizuno R, Tanaka N et al (2019) Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients. Int J Clin Oncol 24(9):1069–1074. https://doi.org/10.1007/s10147-019-01459-1

    Article  PubMed  Google Scholar 

  23. Voss MH, Reising A, Cheng Y et al (2018) Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncol 19(12):1688–1698. https://doi.org/10.1016/s1470-2045(18)30648-x

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bedke J, Gauler T, Grunwald V et al (2017) Systemic therapy in metastatic renal cell carcinoma. World J Urol 35(2):179–188. https://doi.org/10.1007/s00345-016-1868-5

    Article  CAS  PubMed  Google Scholar 

  25. Pena-Llopis S, Christie A, Xie XJ et al (2013) Cooperation and antagonism among cancer genes: the renal cancer paradigm. Can Res 73(14):4173–4179. https://doi.org/10.1158/0008-5472.CAN-13-0360

    Article  CAS  Google Scholar 

  26. Liu W, Fu Q, An H et al (2015) Decreased expression of SETD2 predicts unfavorable prognosis in patients with nonmetastatic clear-cell renal cell carcinoma. Medicine 94(45):e2004. https://doi.org/10.1097/MD.0000000000002004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang J, Liu L, Qu Y et al (2016) Prognostic value of SETD2 expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. J Urol 196(5):1363–1370. https://doi.org/10.1016/j.juro.2016.06.010

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by Grant number 18ZR1423200 form Shanghai Science and Technology Commission Research Project, PYXJS16-008 from the Incubating Program for Clinical Research and Innovation of Renji Hospital, 16CR3062B from 3-year action program of Shanghai Hospital Development Center.

Author information

Author notes

  1. Wen Cai, Zaoyu Wang and Biao Cai have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Pudong District, Shanghai, 200127, People’s Republic of China

    Wen Cai, Biao Cai, Yichu Yuan, Wen Kong, Jin Zhang, Yonghui Chen, Yiran Huang, Jiwei Huang & Wei Xue

  2. Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Rd., Pudong District, Shanghai, 200127, People’s Republic of China

    Zaoyu Wang & Qiang Liu

Authors
  1. Wen Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zaoyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Biao Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yichu Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yonghui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yiran Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiwei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yiran Huang, Jiwei Huang or Wei Xue.

Ethics declarations

Conflict of interest

All the authors declare no conflict of interest.

Human and animal participant rights statement

All the procedures performed in studies involving human participants were in accordance with the ethical standards of the Renji Hospital and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, W., Wang, Z., Cai, B. et al. Expression of PBRM1 as a prognostic predictor in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitor. Int J Clin Oncol 25, 338–346 (2020). https://doi.org/10.1007/s10147-019-01564-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-019-01564-1

Keywords

Search

Navigation