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Year : 2014  |  Volume : 139  |  Issue : 3  |  Page : 337-338

Allelic variability in PSA & AR genes: A novel biomarker on the horizon for carcinoma prostate


Department of Urology All India Institute of Medical Sciences, Ansari Nagar New Delhi 110 029, India

Date of Web Publication9-May-2014

Correspondence Address:
P N Dogra
Department of Urology All India Institute of Medical Sciences, Ansari Nagar New Delhi 110 029
India
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Source of Support: None, Conflict of Interest: None


PMID: 24820826

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How to cite this article:
Dogra P N. Allelic variability in PSA & AR genes: A novel biomarker on the horizon for carcinoma prostate. Indian J Med Res 2014;139:337-8

How to cite this URL:
Dogra P N. Allelic variability in PSA & AR genes: A novel biomarker on the horizon for carcinoma prostate. Indian J Med Res [serial online] 2014 [cited 2020 Jul 2];139:337-8. Available from: http://www.ijmr.org.in/text.asp?2014/139/3/337/132164

Prostate specific antigen (PSA) is an androgen regulated serine protease produced by secretory epithelial cells lining of normal prostatic glands as well as in the majority of prostatic cancer [1],[2] . PSA expression has been the most extensively used marker for prostate cancer screening and gauging the therapeutic response following an intervention [1],[2] . The serum PSA concentration greater than 4 ng/ml is generally considered as an indicator of a potential prostatic abnormality which warrants a further screening by means of prostate needle biopsy [3] . However, PSA testing has been plagued by numerous controversies and a low sensitivity and specificity for detecting prostate cancer due to numerous factors such as presence of non-cancerous prostatic diseases (i.e. prostatitis or benign prostatic hyperplasia) which are very common in India and its variation among different ages and races [4] . To negate the effect of age and race to serum PSA levels there are age- and race-specific cut-off values for serum PSA testing [5],[6] . However, there still remains substantial controversy regarding the use of such cut-offs as these are weighed down by further decreased sensitivity for detection of prostate cancer [7] .

The PSA gene contains a 6-kb promoter in the 5′ region that contributes to tissue and hormone specificity of PSA expression [8],[9],[10] . This promoter contains androgen-responsive elements (AREs) that regulate promoter activity by binding to androgen receptors. ARE I and II are located in the proximal region of the PSA promoter centered at -170 base pairs (bp) and -394 bp, respectively while ARE III is located in the 5′ upstream enhancer region, centered at -4200 bp with respect to the transcription start site [8],[9],[10],[11] . ARE I and ARE III are both found to have high affinities for the androgen receptor, whereas ARE II has a low affinity for the androgen receptor [11],[12],[13],[14] . Further research into these promoter regions has demonstrated the presence of additional high, medium, and low-affinity AREs within the 5′ upstream enhancer region of the PSA promoter located between -3870 bp and -4366 bp with respect to the transcription start site [14] . Chavan et al[15] in their study in this issue have calculated the influence of genetic variants exhibited by PSA and androgen receptor (AR) genes towards the variable expression of PSA in prostate cancer.[TAG:2][TAG:2]

PSA genotype analysis in promoter region and AR gene microsatellite Cytosine / Adenine / Guanine (CAG) repeat analysis in exon 1 region was studied. They found SNPs 158G/A in the proximal promoter region and -3845G/A in enhancer region to be significantly (P<0.001) associated with serum PSA levels [15] . The carriers of homozygous GG genotype showed higher expression of PSA whereas homozygous AA genotype carriers demonstrated lower PSA levels. The authors also found that homozygous GG genotype along with AR long CAG repeats and homozygous AA genotype along with AR short CAG repeats at position -3845 and -158 showed strong interaction and thus synergistically influenced serum PSA levels. Xue et al[16] in their study of 420 healthy men from a multiethnic cohort found that men with PSA AA genotype and short AR CAG alleles have higher PSA levels. Cramer et al[17] found -4643 /A SNP (G allele) is associated with higher mean PSA levels. These studies have further emphasised the enigma of the cut-off level for PSA [16-19] . The role of PSA as a screening marker for prostate cancer has been severely questioned following the Prostate, lung, colorectal and ovarian (PLCO) cancer screening trial [19] . To incorporate SNP in the promoter region of PSA gene into the genetic model for prostate cancer may help in improving the sensitivity and specificity of PSA as a screening tool but these studies need to be taken on a larger scale preferably on a prospective multicentric and multiethnic group to validate these findings.

 
   References Top

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7.Bassler TJ Jr, Orozco R, Bassler IC, O'Dowd GJ, Stamey TA. Most prostate cancers missed by raising the upper limit of normal prostate-specific antigen for men in their sixties are clinically significant. Urology 1998; 52 : 1064-9.  Back to cited text no. 7
    
8.Cleutjens KB, van der Korput HA, van Eekelen CC, van Rooij HC, Faber PW, Trapman J. An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol Endocrinol 1997; 11 : 148-61.  Back to cited text no. 8
    
9.Schuur ER, Henderson GA, Kmetec LA, Miller JD, Lamparski HG, Henderson DR. Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 1996; 271 : 7043-51.  Back to cited text no. 9
    
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11.Cleutjens KB, van Eekelen CC, van der Korput HA, Brinkmann AO, Trapman J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem 1996; 271 : 6379-88.  Back to cited text no. 11
    
12.Pang S, Taneja S, Dardashti K, Cohan P, Kaboo R, Sokoloff M, et al. Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer. Hum Gene Ther 1995; 6 : 1417-26.  Back to cited text no. 12
    
13.Zhang S, Murtha PE, Young CY. Defining a functional androgen responsive element in the 5′ far upstream flanking region of the prostate-specific antigen gene. Biochem Biophys Res Commun 1997; 231 : 784-8.  Back to cited text no. 13
    
14.Zhang J, Zhang S, Murtha PE, Zhu W, Hou SS, Young CY. Identification of two novel cis-elements in the promoter of the prostate-specific antigen gene that are required to enhance androgen receptor-mediated transactivation. Nucleic Acids Res 1997; 25 : 3143-50.  Back to cited text no. 14
    
15.Chavan SV, Maitra A, Roy N, Chavan PR. Contribution of allelic variability in prostate specific antigen (PSA) & androgen receptor (AR) genes to serum PSA levels in men with prostate cancer. Indian J Med Res 2014; 139 : 371-8.   Back to cited text no. 15
    
16.Xue WM, Coetzee GA, Ross RK, Irvine RI, Kolonel RL, Henderson BE, et al. Genetic determinants of serum prostate-specific antigen levels in healthy men from a multiethnic cohort. Cancer Epidemiol Biomarkers Prev 2001; 10 : 575-9.  Back to cited text no. 16
    
17.Cramer SD, Chang B-L, Rao A, Hawkins GA, Zheng SL, Wade WN, et al. Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels. J Natl Cancer Inst 2003; 95 : 1044-53.  Back to cited text no. 17
    
18.Huang W, Shostak Y, Tarr P, Sawyers C, Carey M. Cooperative assembly of androgen receptor into a nucleoprotein complex that regulates the prostate-specific antigen enhancer. J Biol Chem 1999; 274 : 25756-68.  Back to cited text no. 18
    
19.Schröder FH, Hugosson J, Roobol MJ, Tammela TLJ, Ciatto S, Nelen V, et al; ERSPC Investigators. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366 : 981-90.  Back to cited text no. 19
    




 

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