Prostate specific antigen

From Wikipedia, the free encyclopedia

Kallikrein-related peptidase 3
Identifiers
Symbol(s) KLK3; APS; KLK2A1; PSA; hK3
External IDs OMIM: 176820 MGI: 892021 HomoloGene: 84789
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 354 16617
Ensembl ENSG00000142515 ENSMUSG00000063713
Uniprot P07288 O35307
Refseq NM_001030047 (mRNA)
NP_001025218 (protein)		 XM_001000656 (mRNA)
XP_001000656 (protein)
Location Chr 19: 56.05 - 56.06 Mb Chr 7: 44.06 - 44.06 Mb
Pubmed search [1] [2]

Prostate specific antigen (PSA) is a protein produced by the cells of the prostate gland. PSA is present in small quantities in the serum of normal men, and is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is the most effective test currently available for the early detection of prostate cancer. Rising levels of PSA over time are associated with both localized and metastatic prostate cancer (CaP).

Contents

[edit] Biochemistry

Prostate specific antigen (PSA), also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen) is a 34 kD glycoprotein manufactured almost exclusively by the prostate gland; PSA is produced for the ejaculate where it liquifies the semen and allows sperm to swim freely.[1] It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm.[2]

Biochemically it is a serine protease (EC 3.4.21.77) enzyme, the gene of which is located on the nineteenth chromosome (19q13). [3]

[edit] Clinical significance

[edit] Serum PSA

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA
Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA [4]

PSA is normally present in the blood at very low levels. The reference range of 0-4.0 ng/mL for the first commercial PSA test, the Hybritech Tandem-R PSA test released in February 1986, was based on a study that found 99% of 472 apparently healthy men had a total PSA level below 4 ng/mL—the upper limit of normal is much less than 4 ng/mL.[5] Increased levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative.[6] Obesity has been reported to reduce serum PSA levels.[7] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.[8]

PSA levels can be also increased by prostate infection, irritation, benign prostatic hypertrophy (enlargement) or hyperplasia (BPH), and recent ejaculation,[9][10] producing a false positive result. Digital rectal examination (DRE) has been shown in several studies[11] to produce an increase in PSA. However, the effect is clinically insignificant, since DRE causes the most substantial increases in patients with PSA levels already elevated over 4.0 ng/mL.

Despite earlier findings,[12] recent research suggests that the rate of increase of PSA (the PSA velocity) is not a more specific marker for prostate cancer.[13] However, the PSA rate of rise may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy.[14]

Most PSA in the blood is bound to serum proteins. A small amount is not protein bound and is called free PSA. In men with prostate cancer the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. (See graph at right.) The lower the ratio the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.[15] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.[9]

[edit] Other biologic fluids & tissues

Concentration of PSA in human body fluids
Fluid PSA (ng/mL)
semen
200,000 to 5.5 million
amniotic fluid
0.60-8.98
breast milk
0.47-100
saliva
0
female urine
0.12-3.72
female serum
0.01-.53

It is now clear that the term prostate specific antigen is a misnomer. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues.[16]

Other than semen, the greatest concentrations of PSA in biological fluids are detected in breast milk and amniotic fluid. Low concentrations of PSA have been identified in the urethral glands, endometrium, normal breast tissue and salivary gland tissue. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer.[17]

Tissue samples can be stained for the presence of PSA in order to determine the origin of maligant cells that have metastasized.[18]

[edit] Prostate cancer screening

Main article: Prostate cancer screening

The U.S. Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men of age 50 and older. PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious and should be followed by rectal ultrasound imaging and, if indicated, prostate biopsy. PSA is false positive-prone (7 out of 10 men in this category will still not have prostate cancer) and false negative-prone (2.5 out of 10 men with prostate cancer have no elevation in PSA).[19] Recent reports indicate that refraining from ejaculation 24 hours or more prior to testing will improve test accuracy.[9]

[edit] Forensic identification of semen

PSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases.[20] PSA is now used to indicate the presence of semen in forensic serology[21]. The semen of adult males has PSA levels far in excess of those found in other tissues, therefore, a high level of PSA found in a sample is an indicator that semen may be present. Because PSA is a biomarker that is expressed independently of spermatazoa, it remains useful in identifying semen from vasectomized and azoospermic males.[22]

It is important to note that PSA can also be found at low levels in other body fluids, such as urine and breast milk, thus setting a high minimum threshold of interpretation to rule out false positive results is necessary to conclusively state that semen is present.[16] While traditional tests such as crossover electrophoresis have a sufficiently low sensitivity to only detect seminal PSA, newer diagnostics tests developed from clinical prostate cancer screening methods have lowered the threshold of detection down to 4ng/mL.[23] This level of antigen has been shown to be present in the peripheral blood of males with prostate cancer, and rarely in female urine samples and breast milk.[16] No studies have been performed to assess the PSA levels in the tissues and secretions of pre-pubescent children. Therefore, the presence of PSA from a high sensitivity (4ng/mL) test cannot conclusively identify the presence of semen, so care must be taken with the interpretation of such results.

[edit] See also

[edit] References

  1. ^ Steven P. Balk, Yoo-Joung Ko, Glenn J. Bubley (2003). "Biology of Prostate-Specific Antigen" (Abstract). Journal of Clinical Oncology 28 (2): 383-91. 
  2. ^ "Chapter 8: What is the prostate and what is its function?", American Society of Andrology Handbook. Retrieved on 2006-09-17. 
  3. ^ Lilja H. (Nov 2003). "Biology of Prostate-Specific Antigen". Urology 62 ((5 Suppl 1)): 27-33. doi:10.1016/S0090-4295(03)00775-1. PMID 14607215. 
  4. ^ Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A, Richie J, deKernion J, Walsh P, Scardino P, Lange P, Subong E, Parson R, Gasior G, Loveland K, Southwick P (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): 1542-7. doi:10.1001/jama.279.19.1542. PMID 9605898. 
  5. ^ Kolota, Gina (May 30, 2004). "It Was Medical Gospel, but It Wasn't True". The New York Times: p. 4.7. 
    Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA Jr (May 27, 2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter". N Engl J Med 350 (22): 2239-46. PMID 15163773. 
    Carter HB (May 27, 2004). "Prostate cancers in men with low PSA levels--must we find them?". N Engl J Med 350 (22): 2292-4. PMID 15163780. 
    Mytrle JF, Klimley PG, Ivor L, Bruni JF (1986). "Clinical utility of prostate specific antigen (PSA) in the management of prostate cancer", Advances in Cancer Diagnostics. San Diego: Hybritech Inc. 
    Mytrle JF, Ivor L (1989). "Measurement of Prostate-Specific Antigen (PSA) in Serum by a Two-Site Immunometric Method (Hybritech Tandem®-R/Tandem®-E PSA)", Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16-19, 1988 at Prout's Neck, Maine, U.S.A.. New York: Elsevier, pp. 161-71. ISBN 0-444-01514-0. 
    Mytrle JF (1989). "Normal Levels of Prostate-Specific Antigen (PSA)", Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16-19, 1988 at Prout's Neck, Maine, U.S.A.. New York: Elsevier, pp. 183-9. ISBN 0-444-01514-0. 
    Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL (April 25, 1991). "Measurement of prostate-specific antigen in serum as a screening test for prostate cancer". N Engl J Med 324 (17): 1156-61. PMID 1707140. 
    Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, et al. (May 1994). "Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men". J Urol 151 (5): 1283-90. PMID 7512659. 
  6. ^ Thompson I, Pauler D, Goodman P, Tangen C, Lucia M, Parnes H, Minasian L, Ford L, Lippman S, Crawford E, Crowley J, Coltman C (2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter.". N Engl J Med 350 (22): 2239-46. PMID 15163773. 
  7. ^ Bañez LL, Hamilton RJ, Partin AW, Vollmer RT, Sun L, Rodriguez C, Wang Y, Terris MK, Aronson WJ, Presti JC Jr, Kane CJ, Amling CL, Moul JW, Freedland SJ. (2004). "Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer.". JAMA 350 (19): 2275-80. PMID 18029831. 
  8. ^ Robert Dreicer (2007-11-20). "Why Do Obese Men Have Lower PSA Concentrations?". Journal Watch. New England Journal of Medicine. 
  9. ^ a b c Herschman JD, Smith DS, Catalona WJ (1997). "Effect of ejaculation on serum total and free prostate-specific antigen concentrations". Urology 50 (2): 239-43. 
  10. ^ Nadler RB; Humphrey PA; Smith DS; Catalona WJ; Ratliff TL (1995). "Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels". Journal of Urology 154 (2 Pt 1): 407-13. 
  11. ^ Crawford ED, Schutz MJ, Clejan S, Drago J, Resnick MI, Chodak GW, Gomella LG, Austenfeld M, Stone NN, Miles BJ, et al (1992). "The effect of digital rectal examination on prostate-specific antigen levels". JAMA 267 (16): 2227-8. PMID 1372943. 
    Chybowski FM, Bergstralh EJ, Oesterling JE (1992). "The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study". J Urol 148 (1): 83-6. PMID 1377290. 
    Collins GN, Martin PJ, Wynn-Davies A, Brooman PJ, O'Reilly PH (1997). "The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study". J Urol 157 (5): 1744-7. PMID 9112518. 
    Tarhan F, Orçun A, Küçükercan I, Camursoy N, Kuyumcuoğlu U (2005). "Effect of prostatic massage on serum complexed prostate-specific antigen levels". Urology 66 (6): 1234-8. doi:10.1016/j.urology.2005.06.077. PMID 16360449. 
  12. ^ {Carter H, Pearson J, Metter E, Brant L, Chan D, Andres R, Fozard J, Walsh P (1992). "Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease.". JAMA 267 (16): 2215-20. doi:10.1001/jama.267.16.2215. PMID 1372942. 
  13. ^ H. Ballentine Carter (2006). "Assessing Risk: Does This Patient Have Prostate Cancer?" (Editorial). Journal of the National Cancer Institute 98 (8): 506-7. 
  14. ^ D'Amico A, Chen M, Roehl K, Catalona W (2004). "Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy.". N Engl J Med 351 (2): 125-35. doi:10.1056/NEJMoa032975. PMID 15247353. 
  15. ^ Catalona W, Smith D, Ornstein D (1997). "Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements.". JAMA 277 (18): 1452-5. doi:10.1001/jama.277.18.1452. PMID 9145717. 
  16. ^ a b c Dale L. Laux, M.S. & Sarah E. Custis. "Forensic Detection of Semen III. Detection of PSA Using Membrane Based Tests: Sensitivity Issues with Regards to the Presence of PSA in Other Body Fluids" (PDF). . Midwestern Association of Forensic Scientists Retrieved on 2008-05-11.
  17. ^ Stanley A Brosman, eMedicine: Prostate-Specific Antigen, WebMD, <http://www.emedicine.com/med/TOPIC3465.HTM#section~CharacteristicsofProstateSpecificAntigen>. Retrieved on 11 May 2008 
  18. ^ Chuang AY, Demarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI (2007). "Immunohistochemical Differentiation of High-grade Prostate Carcinoma From Urothelial Carcinoma" 31 (8): 1246-1255. doi:10.1097/PAS.0b013e31802f5d33. PMID 17667550. 
  19. ^ Thompson I, Pauler D, Goodman P, Tangen C, Lucia M, Parnes H, Minasian L, Ford L, Lippman S, Crawford E, Crowley J, Coltman C (2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter.". N Engl J Med 350 (22): 2239-46. PMID 15163773. 
  20. ^ Hara M, Inorre T, Fukuyama T. (1971), “Some physicochemical characteristics of gamma-seminoprotein, an antigenic component specific for human seminal plasma”, Jpn J Legal Med. 25: 322-324 
  21. ^ Bill O. Gartside, Kevin J. Brewer & Carmella L. Strong (April 2003), “Estimation of Prostate-Specific Antigen (PSA) Extraction Efficiency from Forensic Samples Using the Seratecâ PSA Semiquant Semiquantitative Membrane Test”, Forensic Science Communications 5 (2), <http://www.fbi.gov/hq/lab/fsc/backissu/april2003/gartside.htm>. Retrieved on 11 May 2008 
  22. ^ M. Hochmeister, O. Rudin, U.V.Borer, A. Kratzer, Ch. Gehrig and R. Dirnhofer (1997). "Evaluation of Prostate-Specific Antigen (PSA) Membrane Tests for the Forensic Identification of Semen". . Eighth International Symposium on Human Identification Retrieved on 2008-05-11.
  23. ^ Manfred N. Hochmeister, Bruce Budowle, Oskar Rudin, Christian Gehrig, Urs Borer, Michael Thali, and Richard Dirnhofer (1999), “Evaluation of Prostate-Specific Antigen (PSA) Membrane Test Assays for the Forensic Identification of Seminal Fluid”, Journal of Forensic Science 44: 1057-60, <http://projects.nfstc.org/workshops/resources/articles/Evaluation%20of%20prostate-specific%20antigen%20(PSA)%20membrane%20test%20assays%20for%20the%20forensic%20identification%20of%20seminal%20fluid.pdf>. Retrieved on 11 May 2008 

[edit] Further reading

  • De Angelis G, Rittenhouse HG, Mikolajczyk SD, Blair Shamel L, Semjonow A (2007). "Twenty Years of PSA: From Prostate Antigen to Tumor Marker". Reviews in urology 9 (3): 113–23. PMID 17934568. 
  • Henttu P, Vihko P (1994). "Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate.". Ann. Med. 26 (3): 157-64. PMID 7521173. 
  • Diamandis EP, Yousef GM, Luo LY, et al. (2001). "The new human kallikrein gene family: implications in carcinogenesis.". Trends Endocrinol. Metab. 11 (2): 54-60. PMID 10675891. 
  • Lilja H (2003). "Biology of prostate-specific antigen.". Urology 62 (5 Suppl 1): 27-33. doi:10.1016/S0090-4295(03)00775-1. PMID 14607215. 

[edit] External links

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