Copy number alterations are associated with metastatic-lethal progression in prostate cancer

Abstract

Backgrounds

Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression.

Methods

Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least 5 years: (1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n = 323 patients); and (2) an Eastern Virginia (EV) Medical School-based cohort (n = 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death.

Results

We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p < 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p < 0.05) when adjusting for Gleason score.

Conclusions

This study shows that CNAs can be reliably detected from HM450K-based DNA methylation data. There are 11 recurrent CNAs showing association with metastatic-lethal events following RP and improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: CONSORT diagrams.
Fig. 2: Tuning of cutoffs for the HM450K-based CNA detection method.
Fig. 3: RCNA regions detected by GISTIC2.0 on the FH dataset.
Fig. 4: The validated 11 RCNAs (adjusting for Gleason score).

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: A Cancer J Clin. 2020;70:7–30.

    Google Scholar 

  2. 2.

    Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA.1999;281:1591–7.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Roehl KA, Han M, Ramos CG, Antenor JAV, Catalona WJ. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol. 2004;172:910–4.

    PubMed  Article  Google Scholar 

  4. 4.

    Bruce JY, Lang JM, McNeel DG, Liu G. Current controversies in the management of biochemical failure in prostate cancer. Clin Adv Hematol Oncol. 2012;10:716–22.

    PubMed  Google Scholar 

  5. 5.

    American Urological Association. 2017 AUA Clinical Guidelines. https://www.auanet.org/guidelines/prostate-cancer-clinically-localized-guideline.

  6. 6.

    Moyer VA. Screening for prostate cancer: US preventive services task force recommendation statement. Ann Intern Med. 2012;157:120–34.

    PubMed  Article  Google Scholar 

  7. 7.

    Delpierre C, Lamy S, Kelly-Irving M, Molinié F, Velten M, Tretarre B, et al. Life expectancy estimates as a key factor in over-treatment: the case of prostate cancer. Cancer Epidemiol. 2013;37:462–8.

    PubMed  Article  Google Scholar 

  8. 8.

    Lee YJ, Park JE, Jeon BR, Lee SM, Kim SY, Lee YK. Is prostate-specific antigen effective for population screening of prostate cancer? A systematic review. Ann Lab Med. 2013;33:233–41.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Klotz J. The future of active surveillance. Transl Androl Urol. 2018;7:256–9.

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    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  Article  Google Scholar 

  11. 11.

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

    Article  CAS  Google Scholar 

  12. 12.

    Grasso CS, Wu Y, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castrate resistant prostate cancer. Nature. 2012;487:239–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Liu W. DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer. Asian J Androl. 2016;18:533–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    El Gammal AT, Brüchmann M, Zustin J, Isbarn H, Hellwinkel OJ, Köllermann J, et al. Chromosome 8p deletions and 8q gains are associated with tumor progression and poor prognosis in prostate cancer. Clin Cancer Res. 2010;16:56–64.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kluth M, Runte F, Barow P, Omari J, Abdelaziz ZM, Paustian L, et al. Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer. Int J Cancer. 2015;137:2354–63.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Lalonde E, Ishkanian A, Sykes J. 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  Article  PubMed Central  Google Scholar 

  18. 18.

    Choucair K, Ejdelman J, Brimo F, Aprikian A, Chevalier S, Lapointe J. PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity. BMC Cancer. 2012;12:543.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, et al. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer. 2011;17:6563–73.

    CAS  Article  Google Scholar 

  20. 20.

    Liu W, Xie CC, Thomas CY, Kim ST, Lindberg J, Egevad L, et al. Genetic markers associated with early cancer‐specific mortality following prostatectomy. Cancer. 2013;119:2405–12.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y, et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci. 2014;111:11139–44.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Feber A, Guilhamon P, Lechner M, Fenton T, Wilson GA, Thirlwell C. Using high-density DNA methylation arrays to profile copy number alterations. Genome Biol. 2014;15:R30.

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Nordlund J, Bäcklin CL, Zachariadis V, Cavelier L, Dahlberg J, Öfverholm I, et al. DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia. Clin Epigenetics. 2015;7:11.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Kwee I, Rinaldi A, Rancoita P, Rossi D, Capello D, Forconi F, et al. Integrated DNA copy number and methylation profiling of lymphoid neoplasms using a single array. Br J Haematol. 2012;156:354–7.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Chao S, Kim H, Zeiger MA, Umbricht CB, Cope LM. Measuring DNA copy number variation using high-density methylation microarrays. J Comput Biol. 2019;26:295–304.

    Article  CAS  Google Scholar 

  26. 26.

    Rubicz R, Zhao S, Wright JL, Coleman L, Grasso CS, Geybels MS, et al. Gene expression panel predicts metastatic‐lethal prostate cancer outcomes in men diagnosed with clinically localized prostate cancer. Mol Oncol. 2017;11:140–50.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Cheng A, FitzGerald LM, Wright JL, Kolb S, Karnes RJ, Kenkins RB, et al. A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: development and validation studies. Prostate. 2019;79:1589–96.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Zhao S, Geybels MS, Leonardson A, Rubicz R, Kolb S, Yan Q, et al. Epigenome-wide tumor DNA methylation profiling identifies novel prognostic biomarkers of metastatic-lethal progression in men diagnosed with clinically localized prostate cancer. Clin Cancer Res. 2017;23:311–9.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Zhao S, Leonardson A, Geybels MS, McDaniel AS, Yu M, Kolb S, et al. A five-CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer. Prostate. 2018;78:1084–91.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  30. 30.

    Stanford JL, Wicklund KG, McKnight B, Daling JR, Brawer MK. Vasectomy and risk of prostate cancer. Cancer Epidemiol Biomark Prev. 1999;8:881–6.

    CAS  Google Scholar 

  31. 31.

    Agalliu I, Salinas CA, Hansten PD, Ostrander EA, Stanford JL. Statin use and risk of prostate cancer: results from a population-based epidemiologic study. Am J Epidemiol. 2008;168:250–60.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le JM, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011;98:288–95.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Morris TJ, Butcher LM, Feber A. ChAMP: 450k chip analysis methylation pipeline. Bioinformatics. 2014;30:428–30.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Tian Y, Morris TJ, Webster AP. ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics. 2017;33:3982–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Seshan VE, Olshen A, DNAcopy: DNA copy number data analysis. R package version 1.56.0;2018.

  36. 36.

    Merme lGH, Schumacher SE, Hill B. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12:R41.

    Article  CAS  Google Scholar 

  37. 37.

    Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JZ. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform. 2011;12:77.

    Article  Google Scholar 

  38. 38.

    Whitton B, Okamoto H, Packham G, Crabb SJ. Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer. Cancer Med. 2018;7:3800–11.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Li B, Thrasher JB, Terranova P. Glycogen synthase kinase-3: a potential preventive target for prostate cancer management. Urol Oncol. 2015;33:456–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Kobayashi N, Uemura H, Nagahama K. Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget. 2012;3:1455–71.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Song Y, Song C, Yang S. Tumor-suppressive function of miR-30d-5p in prostate cancer cell proliferation and migration by targeting NT5E. Cancer Biother Radiopharm. 2018;33:203–11.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Wang R, Asangani IA, Chakravarthi BV, Ateeq B, Lonigro RJ, Cao Q, et al. Role of transcriptional corepressor CtBP1 in prostate cancer progression. Neoplasia. 2012;14:905–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Bluemn EG, Spencer ES, Mecham B, Gordon RR, Coleman I, Lewinshtein D, et al. PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality. Mol Cancer Res. 2013;11:568–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Vainio P, Gupta S, Ketola K, Mirtti T, Mpindi J, Kohonen P, et al. Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. Am J Pathol. 2011;178:525–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8:253–67.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Zhang Z, She J, Yang J. NDRG4 in gastric cancer determines tumor cell proliferation and clinical outcome. Mol Carcinog. 2018;57:762–71.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Hail N, Chen P, Bushman LR. Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention. Neoplasia. 2010;12:464–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Yang L, Ravindranathan P, Ramanan M, Kapur P, Hammes SR, Hsieh J, et al. Central role for PELP1 in nonandrogenic activation of the androgen receptor in prostate cancer. Mol Endocrinol. 2012;26:550–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Kluth M, Jung S, Habib O, Eshagzaiy M, Heinl A, Amschler N, et al. Deletion lengthening at chromosomes 6q and 16q targets multiple tumor suppressor genes and is associated with an increasingly poor prognosis in prostate cancer. Oncotarget. 2017;8:108923–35.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Osman I, Scher H, Daibacni G, Reuter V, Zhang Z, Cordon-Cardo C. Chromosome 16 in primary prostate cancer: a microsatellite analysis. Int J Cancer. 1997;71:580–4.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Cancer Institute (R01 CA222833, R01 CA056678, R01 CA092579, K05 CA175147 (JLS), and P50 CA097186), with additional support provided by the Fred Hutchinson Cancer Research Center (P30 CA015704). We acknowledge the support of the Eastern Virginia Medical School Biorepository, Norfolk, Virginia.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Xiaoyu Wang or Janet L. Stanford.

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

Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Grasso, C.S., Jordahl, K.M. et al. Copy number alterations are associated with metastatic-lethal progression in prostate cancer. Prostate Cancer Prostatic Dis (2020). https://doi.org/10.1038/s41391-020-0212-8

Download citation