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
  • Clinical Research
  • Published:

TP53 alterations of hormone-naïve prostate cancer in the Chinese population

Prostate Cancer and Prostatic Diseases volume 24, pages 482–491 (2021)Cite this article

Subjects

Abstract

Background

Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations.

Methods

We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations.

Results

The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT–ribose polymerase (PARP) inhibitors.

Conclusions

Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Significant genomic alterations in PCa.
Fig. 2: Landscape of genomic alterations in PCa.
Fig. 3: Alterations of genes in the cancer-related pathway found in PCa.
Fig. 4: Landscape of actionable alterations with OncoKB recommendations in PCa.

Similar content being viewed by others

References

  1. Rebecca LS, Kimberly DM, Ahmedin J. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Google Scholar 

  2. Buttigliero C, Tucci M, Bertaglia V, Vignani F, Bironzo P, Di Maio M, et al. Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer. Cancer Treat Rev. 2015;41:884–92.

    CAS  PubMed  Google Scholar 

  3. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.

    PubMed  Google Scholar 

  4. Chen R, Ren S, Yiu MK, Fai NC, Cheng WS, Ian LH. Chinese Prostate Cancer Consortium et al. Prostate cancer in Asia: a collaborative report. Asian J Urol. 2014;1:15–29.

    PubMed  Google Scholar 

  5. Ren S, Wei GH, Liu D, Wang L, Hou Y, Zhu S, et al. Whole-genome and transcriptome sequencing of prostate cancer identify new genetic alterations driving disease progression. Eur Urol. 2018;73:322–39.

    CAS  PubMed  Google Scholar 

  6. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl J Med. 2014;371:424–33.

    PubMed  PubMed Central  Google Scholar 

  7. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl J Med. 2011;364:1995–2005.

    PubMed  PubMed Central  Google Scholar 

  8. Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. 2017;35:3189–97.

    CAS  PubMed  Google Scholar 

  9. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer. Eur Urol. 2019;76:89–97.

    CAS  PubMed  Google Scholar 

  12. De Laere B, Oeyen S, Mayrhofer M, Whitington T, van Dam PJ, Van Oyen P, et al. TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25:1766–73.

    PubMed  Google Scholar 

  13. Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017;541:359–64.

    CAS  PubMed  Google Scholar 

  14. Beltran H, Yelensky R, Frampton GM, Park K, Downing SR, MacDonald TY, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013;63:920–6.

    CAS  PubMed  Google Scholar 

  15. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Google Scholar 

  16. Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004;4:793–805.

    CAS  PubMed  Google Scholar 

  17. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl J Med. 1995;332:1393–8.

    CAS  PubMed  Google Scholar 

  18. Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest. 2020;130:1743–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl J Med. 2020;382:2091–102.

    PubMed  Google Scholar 

  20. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl J Med. 2015;372:2509–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5:471–8.

    PubMed  Google Scholar 

  22. Nava Rodrigues D, Rescigno P, Liu D, Yuan W, Carreira S, Lambros MB, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest. 2018;128:4441–53.

    PubMed  PubMed Central  Google Scholar 

  23. Huang JB, Wu YP, Lin YZ, Cai H, Chen SH, Sun XL, et al. Up-regulation of LIMK1 expression in prostate cancer is correlated with poor pathological features, lymph node metastases and biochemical recurrence. J Cell Mol Med. 2020;24:4698–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gleicher S, Kauffman EC, Kotula L, Bratslavsky G, Vourganti S. Implications of high rates of metastatic prostate cancer in BRCA2 mutation carriers. Prostate. 2016;76:1135–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22:369–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017;1:1–16.

    Google Scholar 

  29. Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erho N, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014;15:1521–32.

    PubMed  Google Scholar 

  30. Buyyounouski MK, Pickles T, Kestin LL, Allison R, Williams SG. Validating the interval to biochemical failure for the identification of potentially lethal prostate cancer. J Clin Oncol. 2012;30:1857–63.

    PubMed  Google Scholar 

  31. Ecke TH, Schlechte HH, Schiemenz K, Sachs MD, Lenk SV, Rudolph BD, et al. TP53 gene mutations in prostate cancer progression. Anticancer Res. 2010;30:1579–86.

    CAS  PubMed  Google Scholar 

  32. Tosoian JJ, Almutairi F, Morais CL, Glavaris S, Hicks J, Sundi D, et al. Prevalence and prognostic significance of PTEN loss in African-American and European-American men undergoing radical prostatectomy. Eur Urol. 2017;71:697–700.

    PubMed  Google Scholar 

  33. Kim SH, Park WS, Yun SI, Joo J, Joung JY, Seo HK, et al. Overexpression of BRCA1 or BRCA2 in prostatectomy specimens is predictive of biochemical recurrence after radical prostatectomy. Histopathology. 2016;68:673–9.

    PubMed  Google Scholar 

  34. Ateeq B, Bhatia V, Goel S. Molecular discriminators of racial disparities in prostate cancer. Trends Cancer. 2016;2:116–20.

    PubMed  PubMed Central  Google Scholar 

  35. Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M, et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep. 2019;28:1370–84.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kunimasa K, Hirotsu Y, Nakamura H, Tamiya M, Iijima Y, Ishida H, et al. Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model. Cancer Genet. 2020;241:51–6.

    CAS  PubMed  Google Scholar 

  37. Yamamoto S, Iwakuma T. Regulators of oncogenic mutant TP53 gain of function. Cancers (Basel). 2018;11:4.

    PubMed Central  Google Scholar 

  38. Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science. 2003;302:1972–5.

    CAS  PubMed  Google Scholar 

  39. Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rajan P, Sudbery IM, Villasevil ME, Mui E, Fleming J, Davis M, et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. Eur Urol. 2014;66:32–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Pinyol R, Sia D, Llovet JM. Immune exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin Cancer Res. 2019;25:2021–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Linch M, Goh G, Hiley C, Shanmugabavan Y, McGranahan N, Rowan A, et al. Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol. 2017;28:2472–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cao H, Liu X, Chen Y, Yang P, Huang T, Song L, et al. Circulating tumor DNA is capable of monitoring the therapeutic response and resistance in advanced colorectal cancer patients undergoing combined target and chemotherapy. Front Oncol. 2020;10:466.

    PubMed  PubMed Central  Google Scholar 

  45. Chen H, Chong W, Wu Q, Yao Y, Mao M, Wang X. Association of LRP1B mutation with tumor mutation burden and outcomes in melanoma and non-small cell lung cancer patients treated with immune check-point blockades. Front Immunol. 2019;10:1113.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Tucker MD, Zhu J, Marin D, Gupta RT, Gupta S, Berry WR, et al. Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Cancer Med. 2019;8:4644–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8:444–57.

    CAS  PubMed  Google Scholar 

  48. Lindberg J, Mills IG, Klevebring D, Liu W, Neiman M, Xu J, et al. The mitochondrial and autosomal mutation landscapes of prostate cancer. Eur Urol. 2013;63:702–8.

    CAS  PubMed  Google Scholar 

  49. Rampias T, Karagiannis D, Avgeris M, Polyzos A, Kokkalis A, Kanaki Z, et al. The lysine-specific methyltransferase KMT2C/MLL3 regulates DNA repair components in cancer. EMBO Rep. 2019;20:e46821.

    PubMed  PubMed Central  Google Scholar 

  50. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol. 2011;29:3659–68.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (NO.81800672) and the Key Research and Development Program of Shandong Province (NO.2017GSF18105 and NO.2019GSF108123).

Author information

Authors and Affiliations

  1. Department of Urology, Qilu Hospital of Shandong University, Ji’nan, 250012, PR China

    Zhengfang Liu, Hu Guo, Yaofeng Zhu, Yangyang Xia, Jianfeng Cui, Kai Shi, Yidong Fan, Benkang Shi & Shouzhen Chen

  2. Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong, Ji’nan, 250012, PR China

    Zhengfang Liu, Hu Guo, Yaofeng Zhu, Yangyang Xia, Jianfeng Cui, Kai Shi, Benkang Shi & Shouzhen Chen

Authors
  1. Zhengfang Liu
    View author publications

    Search author on:PubMed Google Scholar

  2. Hu Guo
    View author publications

    Search author on:PubMed Google Scholar

  3. Yaofeng Zhu
    View author publications

    Search author on:PubMed Google Scholar

  4. Yangyang Xia
    View author publications

    Search author on:PubMed Google Scholar

  5. Jianfeng Cui
    View author publications

    Search author on:PubMed Google Scholar

  6. Kai Shi
    View author publications

    Search author on:PubMed Google Scholar

  7. Yidong Fan
    View author publications

    Search author on:PubMed Google Scholar

  8. Benkang Shi
    View author publications

    Search author on:PubMed Google Scholar

  9. Shouzhen Chen
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Yidong Fan, Benkang Shi or Shouzhen Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Z., Guo, H., Zhu, Y. et al. TP53 alterations of hormone-naïve prostate cancer in the Chinese population. Prostate Cancer Prostatic Dis 24, 482–491 (2021). https://doi.org/10.1038/s41391-020-00302-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41391-020-00302-3

This article is cited by

Search

Advanced search

Quick links