Diagnosis of prostate cancer by detection of minichromosome maintenance 5 protein in urine sediments

T J Dudderidge, J D Kelly, A Wollenschlaeger, O Okoturo, T Prevost, W Robson, H Y Leung, G H Williams, K Stoeber, T J Dudderidge, J D Kelly, A Wollenschlaeger, O Okoturo, T Prevost, W Robson, H Y Leung, G H Williams, K Stoeber

Abstract

Background: The accuracy of prostate-specific antigen (PSA) testing in prostate cancer detection is constrained by low sensitivity and specificity. Dysregulated expression of minichromosome maintenance (Mcm) 2-7 proteins is an early event in epithelial multistep carcinogenesis and thus MCM proteins represent powerful cancer diagnostic markers. In this study we investigate Mcm5 as a urinary biomarker for prostate cancer detection.

Methods: Urine was obtained from 88 men with prostate cancer and from two control groups negative for malignancy. A strictly normal cohort included 28 men with complete, normal investigations, no urinary calculi and serum PSA <2 ng ml(-1). An expanded control cohort comprised 331 men with a benign final diagnosis, regardless of PSA level. Urine was collected before and after prostate massage in the cancer patient cohort. An immunofluorometric assay was used to measure Mcm5 levels in urine sediments.

Results: The Mcm5 test detected prostate cancer with 82% sensitivity (confidence interval (CI)= 72-89%) and with a specificity ranging from 73 (CI=68-78%) to 93% (CI=76-99%). Prostate massage led to increased Mcm5 signals compared with pre-massage samples (median 3440 (interquartile range (IQR) 2280 to 5220) vs 2360 (IQR <1800 to 4360); P=0.009), and was associated with significantly increased diagnostic sensitivity (82 vs 60%; P=0.012).

Conclusions: Urinary Mcm5 detection seems to be a simple, accurate and noninvasive method for identifying patients with prostate cancer. Large-scale prospective trials are now required to evaluate this test in diagnosis and screening.

References

    1. Ayaru L, Stoeber K, Webster GJ, Hatfield AR, Wollenschlaeger A, Okoturo O, Rashid M, Williams G, Pereira SP (2008) Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates. Br J Cancer 98: 1548–1554
    1. Barkley LR, Hong HK, Kingsbury SR, James M, Stoeber K, Williams GH (2007) Cdc6 is a rate-limiting factor for proliferative capacity during HL60 cell differentiation. Exp Cell Res 313: 3789–3799
    1. Chun FK, de la Taille A, van PH, Marberger M, Stenzl A, Mulders PF, Huland H, Abbou CC, Stillebroer AB, van Gils MP, Schalken JA, Fradet Y, Marks LS, Ellis W, Partin AW, Haese A (2009) Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol 56(4): 659–667
    1. Dudderidge TJ, McCracken SR, Loddo M, Fanshawe TR, Kelly JD, Neal DE, Leung HY, Williams GH, Stoeber K (2007) Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. Br J Cancer 96: 1384–1393
    1. Dudderidge TJ, Stoeber K, Loddo M, Atkinson G, Fanshawe T, Griffiths DF, Williams GH (2005) Mcm2, Geminin, and KI67 define proliferative state and are prognostic markers in renal cell carcinoma. Clin Cancer Res 11: 2510–2517
    1. Eward KL, Obermann EC, Shreeram S, Loddo M, Fanshawe T, Williams C, Jung HI, Prevost AT, Blow JJ, Stoeber K, Williams GH (2004) DNA replication licensing in somatic and germ cells. J Cell Sci 117: 5875–5886
    1. Freeman A, Morris LS, Mills AD, Stoeber K, Laskey RA, Williams GH, Coleman N (1999) Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res 5: 2121–2132
    1. Going JJ, Keith WN, Neilson L, Stoeber K, Stuart RC, Williams GH (2002) Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barrett's mucosa. Gut 50: 373–377
    1. Hernandez J, Thompson IM (2004) Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker. Cancer 101: 894–904
    1. Hessels D, Schalken JA (2009) The use of PCA3 in the diagnosis of prostate cancer. Nat Rev Urol 6: 255–261
    1. Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Haggman M, Andersson SO, Spangberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlen BJ (2002) A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347: 781–789
    1. Kearsey SE, Labib K (1998) MCM proteins: evolution, properties, and role in DNA replication. Biochim Biophys Acta 1398: 113–136
    1. Kumar P, Kapoor S, Nargund V (2006) Haematospermia – a systematic review. Ann R Coll Surg Engl 88: 339–342
    1. Lilja H, Ulmert D, Vickers AJ (2008) Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer 8: 268–278
    1. Machida YJ, Hamlin JL, Dutta A (2005) Right place, right time, and only once: replication initiation in metazoans. Cell 123: 13–24
    1. Meng MV, Grossfeld GD, Williams GH, Dilworth S, Stoeber K, Mulley TW, Weinberg V, Carroll PR, Tlsty TD (2001) Minichromosome maintenance protein 2 expression in prostate: characterization and association with outcome after therapy for cancer. Clin Cancer Res 7: 2712–2718
    1. Oesterling JE (1991) Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 145: 907–923
    1. Remus D, Diffley JF (2009) Eukaryotic DNA replication control: lock and load, then fire. Curr Opin Cell Biol 21: 771–777
    1. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Berenguer A, Maattanen L, Bangma CH, Aus G, Villers A, Rebillard X, van der Kwast T, Blijenberg BG, Moss SM, de Koning HJ, Auvinen A (2009) Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360: 1320–1328
    1. Stoeber K, Swinn R, Prevost AT, de Clive-Lowe P, Halsall I, Dilworth SM, Marr J, Turner WH, Bullock N, Doble A, Hales CN, Williams GH (2002) Diagnosis of genito-urinary tract cancer by detection of minichromosome maintenance 5 protein in urine sediments. J Natl Cancer Inst 94: 1071–1079
    1. Stoeber K, Tlsty TD, Happerfield L, Thomas GA, Romanov S, Bobrow L, Williams ED, Williams GH (2001) DNA replication licensing and human cell proliferation. J Cell Sci 114: 2027–2041
    1. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman Jr CA (2005) Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 294: 66–70
    1. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman Jr CA (2003) The influence of finasteride on the development of prostate cancer. N Engl J Med 349: 215–224
    1. Williams GH, Romanowski P, Morris L, Madine M, Mills AD, Stoeber K, Marr J, Laskey RA, Coleman N (1998) Improved cervical smear assessment using antibodies against proteins that regulate DNA replication. Proc Natl Acad Sci USA 95: 14932–14937
    1. Williams GH, Stoeber K (2007) Cell cycle markers in clinical oncology. Curr Opin Cell Biol 19: 672–679
    1. Williams GH, Swinn R, Prevost AT, de Clive-Lowe P, Halsall I, Going JJ, Hales CN, Stoeber K, Middleton SJ (2004) Diagnosis of oesophageal cancer by detection of minichromosome maintenance 5 protein in gastric aspirates. Br J Cancer 91: 714–719

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅