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Systematic, evidence-based discovery of biomarkers at the NCI

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Abstract

In the past decade, biomarker discovery has become ubiquitous in cancer research. However, despite this interest in biomarker research, few newly-characterized biomarkers have emerged as clinically-used entities. Here, we review the current state of biomarker research in cancer and identify challenges that stall many biomarker discovery efforts. We outline a model for systematic biomarker discovery, exemplified by recent efforts in prostate cancer, in which bioinformatics plays a central role in identifying promising new candidate biomarkers. Finally, we review the role of the National Cancer Institute’s Early Detection Research Network (EDRN) in biomarker studies and the importance of EDRN-led efforts to establish a research standard for more effective biomarker discovery efforts.

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References

  1. Srivastava S (2007) Cancer biomarker discovery and development in gastrointestinal cancers: early detection research network:a collaborative approach. Gastrointest Cancer Res 1(4 Suppl 2):S60–S63

    PubMed  Google Scholar 

  2. Sawyers CL (2008) The cancer biomarker problem. Nature 452(7187):548–552

    Article  PubMed  CAS  Google Scholar 

  3. Ransohoff DF (2007) How to improve reliability and efficiency of research about molecular markers: roles of phases, guidelines, and study design. J Clin Epidemiol 60(12):1205–1219

    Article  PubMed  Google Scholar 

  4. Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24(8):971–983

    Article  PubMed  CAS  Google Scholar 

  5. Freidlin B, McShane LM, Korn EL (2010) Randomized clinical trials with biomarkers: design issues. J Natl Cancer Inst 102(3):152–160

    Article  PubMed  CAS  Google Scholar 

  6. Diamandis EP (2010) Cancer biomarkers: can we turn recent failures into success? J Natl Cancer Inst 102(19):1462–1467

    Article  PubMed  CAS  Google Scholar 

  7. Nass SJ (ed) (2007) Committee on developing biomarker-based tools for cancer screening, diagnosis, and treatment. National Academies Press, Washington, DC

    Google Scholar 

  8. Srivastava S, Rossi SC (1996) Early detection research program at the NCI. Int J Cancer 69(1):35–37

    Article  PubMed  CAS  Google Scholar 

  9. Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD (2008) Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design. J Natl Cancer Inst 100(20):1432–1438

    Article  PubMed  CAS  Google Scholar 

  10. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies (remark). Nat Clin Pract Oncol 2(8):416–422

    Article  PubMed  CAS  Google Scholar 

  11. Prensner JR, Rubin MA, Wei JT, Chinnaiyan AM (2012) Beyond PSA: the next generation of prostate cancer biomarkers. Sci Transl Med 4(127):127rv123

    Article  Google Scholar 

  12. Etzioni R, Cha R, Feuer EJ, Davidov O (1998) Asymptomatic incidence and duration of prostate cancer. Am J Epidemiol 148(8):775–785

    Article  PubMed  CAS  Google Scholar 

  13. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL (1991) Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324(17):1156–1161

    Article  PubMed  CAS  Google Scholar 

  14. Makarov DV, Loeb S, Getzenberg RH, Partin AW (2009) Biomarkers for prostate cancer. Annu Rev Med 60:139–151

    Article  PubMed  CAS  Google Scholar 

  15. Brawer MK (1999) Prostate-specific antigen: current status. CA Cancer J Clin 49(5):264–281

    Article  PubMed  CAS  Google Scholar 

  16. Stephan C, Jung K, Lein M, Diamandis EP (2007) PSA and other tissue kallikreins for prostate cancer detection. Eur J Cancer 43(13):1918–1926

    Article  PubMed  CAS  Google Scholar 

  17. Prensner JR, Chinnaiyan AM (2009) Oncogenic gene fusions in epithelial carcinomas. Curr Opin Genet Dev 19(1):82–91

    Article  PubMed  CAS  Google Scholar 

  18. Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao Q, Han B, Yu J et al (2007) Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448(7153):595–599

    Article  PubMed  CAS  Google Scholar 

  19. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C et al (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644–648

    Article  PubMed  CAS  Google Scholar 

  20. Kumar-Sinha C, Tomlins SA, Chinnaiyan AM (2008) Recurrent gene fusions in prostate cancer. Nat Rev Cancer 8(7):497–511

    Article  PubMed  CAS  Google Scholar 

  21. Mani RS, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N, Chinnaiyan AM (2009) Induced chromosomal proximity and gene fusions in prostate cancer. Science 326(5957):1230

    Article  PubMed  CAS  Google Scholar 

  22. Laxman B, Morris DS, Yu J, Siddiqui J, Cao J, Mehra R, Lonigro RJ, Tsodikov A, Wei JT, Tomlins SA, Chinnaiyan AM (2008) A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res 68(3):645–649

    Article  PubMed  CAS  Google Scholar 

  23. Hessels D, Smit FP, Verhaegh GW, Witjes JA, Cornel EB, Schalken JA (2007) Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin Cancer Res 13(17):5103–5108

    Article  PubMed  CAS  Google Scholar 

  24. Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R, Suleman K, Varambally S, Brenner JC, MacDonald T, Srivastava A et al (2010) Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 12(7):590–598

    PubMed  CAS  Google Scholar 

  25. Tomlins SA, Rhodes DR, Yu J, Varambally S, Mehra R, Perner S, Demichelis F, Helgeson BE, Laxman B, Morris DS, Cao Q et al (2008) The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell 13(6):519–528

    Article  PubMed  CAS  Google Scholar 

  26. Ateeq B, Tomlins SA, Laxman B, Asangani IA, Cao Q, Cao X, Li Y, Wang X, Feng FY, Pienta KJ, Varambally S et al (2011) Therapeutic targeting of SPINK1-positive prostate cancer. Sci Transl Med 3(72):72ra17

    Article  PubMed  Google Scholar 

  27. Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q, Cao X, Suleman K, Kumar-Sinha C et al (2010) Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16(7):793–798

    Article  PubMed  CAS  Google Scholar 

  28. Haese A, de la Taille A, van Poppel H, Marberger M, Stenzl A, Mulders PF, Huland H, Abbou CC, Remzi M, Tinzl M, Feyerabend S et al (2008) Clinical utility of the PCA3 urine assay in european men scheduled for repeat biopsy. Eur Urol 54(5):1081–1088

    Article  PubMed  Google Scholar 

  29. Hessels D, Schalken JA (2009) The use of PCA3 in the diagnosis of prostate cancer. Nat Rev Urol 6(5):255–261

    Article  PubMed  CAS  Google Scholar 

  30. Roobol MJ, Schroder FH, van Leeuwen P, Wolters T, van den Bergh RC, van Leenders GJ, Hessels D (2010) Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test. Eur Urol 58(4):475–481

    Article  PubMed  CAS  Google Scholar 

  31. Prensner JR, Chinnaiyan AM (2011) The emergence of lncRNAs in cancer biology. Cancer Discov 1(5):391–407

    Article  PubMed  CAS  Google Scholar 

  32. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD, Cao X et al (2011) Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol 29(8):742–749

    Article  PubMed  CAS  Google Scholar 

  33. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N, Isaacs WB (1999) DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 59(23):5975–5979

    PubMed  CAS  Google Scholar 

  34. de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, Swinkels DW, Schalken JA (2002) DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res 62(9):2695–2698

    PubMed  Google Scholar 

  35. Deras IL, Aubin SM, Blase A, Day JR, Koo S, Partin AW, Ellis WJ, Marks LS, Fradet Y, Rittenhouse H, Groskopf J (2008) PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol 179(4):1587–1592

    Article  PubMed  Google Scholar 

  36. Tomlins SA, Aubin SM, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, Williamsen S, Hodge P, Meinke J, Blase A, Penabella Y et al (2011) Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci Transl Med 3(94):94ra72

    Article  PubMed  CAS  Google Scholar 

  37. Gopalan A, Leversha MA, Satagopan JM, Zhou Q, Al-Ahmadie HA, Fine SW, Eastham JA, Scardino PT, Scher HI, Tickoo SK, Reuter VE et al (2009) TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res 69(4):1400–1406

    Article  PubMed  CAS  Google Scholar 

  38. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK et al (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457(7231):910–914

    Article  PubMed  CAS  Google Scholar 

  39. Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, Bhakoo KK et al (2012) Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148(1–2):259–272

    Article  PubMed  CAS  Google Scholar 

  40. Meyer TE, Fox SD, Issaq HJ, Xu X, Chu LW, Veenstra TD, Hsing AW (2011) A reproducible and high-throughput hplc/ms method to separate sarcosine from alpha- and beta-alanine and to quantify sarcosine in human serum and urine. Anal Chem 83(14):5735–5740

    Article  PubMed  CAS  Google Scholar 

  41. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ et al (2004) Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter. N Engl J Med 350(22):2239–2246

    Article  PubMed  CAS  Google Scholar 

  42. Thompson IM, Pauler Ankerst D, Chi C, Goodman PJ, Tangen CM, Lippman SM, Lucia MS, Parnes HL, Coltman CA Jr (2007) Prediction of prostate cancer for patients receiving finasteride: results from the prostate cancer prevention trial. J Clin Oncol 25(21):3076–3081

    Article  PubMed  CAS  Google Scholar 

  43. Balk SP, Ko YJ, Bubley GJ (2003) Biology of prostate-specific antigen. J Clin Oncol 21(2):383–391

    Article  PubMed  CAS  Google Scholar 

  44. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, deKernion JB, Walsh PC, Scardino PT, Lange PH et al (1998) Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 279(19):1542–1547

    Article  PubMed  CAS  Google Scholar 

  45. Catalona WJ, Smith DS, Wolfert RL, Wang TJ, Rittenhouse HG, Ratliff TL, Nadler RB (1995) Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 274(15):1214–1220

    Article  PubMed  CAS  Google Scholar 

  46. Mikolajczyk SD, Catalona WJ, Evans CL, Linton HJ, Millar LS, Marker KM, Katir D, Amirkhan A, Rittenhouse HG (2004) Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem 50(6):1017–1025

    Article  PubMed  CAS  Google Scholar 

  47. Sokoll LJ, Chan DW, Mikolajczyk SD, Rittenhouse HG, Evans CL, Linton HJ, Mangold LA, Mohr P, Bartsch G, Klocker H, Horninger W et al (2003) Proenzyme PSA for the early detection of prostate cancer in the 2.5–4.0 ng/ml total PSA range: preliminary analysis. Urology 61(2):274–276

    Article  PubMed  Google Scholar 

  48. Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, Broyles DL, Partin AW, Srivastava S, Thompson IM, Wei JT, Zhang Z et al (2010) A prospective, multicenter, national cancer institute early detection research network study of [-2]propsa: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 19(5):1193–1200

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to acknowledge the numerous labs, authors, and publications that we were unable to cite in this review due to space restrictions. This work was supported by the Early Detection Research Network Grant U01 CA 11275 (to A. M. C.), the Department of Defense Grants PC100171 (to A. M. C.) and PC094290 (to J. R. P.), NIH Prostate Specialized Program of Research Excellence grant P50CA69568 (to A. M. C.). A. M. C. is supported by the Doris Duke Charitable Foundation Clinical Scientist Award, the Prostate Cancer Foundation, the American Cancer Society, and the Howard Hughes Medical Institute. J. R. P. is a Fellow of the University of Michigan Medical Scientist Training Program. A. M. C. is a Taubman Scholar of the University of Michigan.

Conflict of interest

A. M. C. serves as an advisor to Gen-Probe, Inc., who has developed diagnostic tests using PCA3 and TMPRSS2-ERG. The University of Michigan has licensed the development of TMPRSS2-ERG-based prostate cancer diagnostic assays to Gen-Probe and A. M. C. is named as a co-inventor. Gen-Probe was not involved in the writing or approval of this manuscript.

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Authors and Affiliations

  1. Michigan Center for Translational Pathology, University of Michigan Medical School, 1400 E. Medical Center Drive, Ann Arbor, MI, 48109, USA

    John R. Prensner & Arul M. Chinnaiyan

  2. Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, Suite 3142, Rockville, MD, 20852, USA

    Sudhir Srivastava

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  1. John R. Prensner
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  2. Arul M. Chinnaiyan
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  3. Sudhir Srivastava
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Correspondence to Sudhir Srivastava.

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Prensner, J.R., Chinnaiyan, A.M. & Srivastava, S. Systematic, evidence-based discovery of biomarkers at the NCI. Clin Exp Metastasis 29, 645–652 (2012). https://doi.org/10.1007/s10585-012-9507-z

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  • DOI: https://doi.org/10.1007/s10585-012-9507-z

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