title: Implication of DNA repair genes in prostate tumourigenesis in Indian males.
abstract: OBJECTIVE
  Prostate cancer (CaP) is the fifth most common cancer among Indian men. Tumour protein p53 (TP53) gene increases the fidelity of DNA replication and homologous recombination by transcriptional transactivation of mismatch repair (MMR) genes. DNA repair thus has a potential role in molecular carcinogenesis of CaP. The aim of the present study was to identify mutations, and polymorphisms in TP53 gene and MMR protein expression in CaP in Indian male population.
  
  
  METHODS
  TP53 codon 72 polymorphism was analysed in 105 CaP, 120 benign prostatic hyperplasia (BPH) cases and 106 normal controls. Mutational analysis of TP53 was done in DNA extracted from formalin fixed paraffin embedded tissue of 80 CaP and 24 BPH cases. Expression of MMR proteins viz. hMLH1, hMSH2, hPMS1 and hPMS2 was studied in 80 CaP, 15 prostatic intraepithelial neoplasia (PIN) and 15 BPH cases.
  
  
  RESULTS
  A somatic C/A variation at the intronic boundary of exon 7 in TP53 gene was observed in one each biopsy samples from CaP and BPH. A significant association of codon 72 TP53 Pro/Pro genotype was observed with the risk of CaP (OR, 2.59, P=0.02) and BPH (OR, 6.27, P<0.001). Immunohistochemical analysis of MMR proteins showed maximum loss of hPMS1 expression in cases of CaP and PIN while no loss in expression of MMR proteins was observed in BPH cases. The study also identified a significant loss of hPMS2 protein in poorly differentiated tumours (Gleason score >7) than in well differentiated tumours (Gleason score 3-6) (P<0.05).
  
  
  CONCLUSIONS
  The results of the present study demonstrate that TP53 codon 72 polymorphism plays significant role in the pathogenesis and susceptibility to CaP and BPH. Also, an aberrant MMR protein expression could be involved in progression of prostate cancer through PIN, early CaP to aggressive CaP. The loss of hPMS2 protein expression may serve as a marker for progression of CaP.
authors.affiliation: National Institute of Pathology (ICMR), New Delhi, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Bansal
authors.forename: Abha
authors.initials: A
authors.lastname: Soni
authors.forename: Punita
authors.initials: P
authors.lastname: Rao
authors.forename: L C
authors.initials: LC
authors.lastname: Singh
authors.forename: Ashwani Kumar
authors.initials: AK
authors.lastname: Mishra
authors.forename: N K
authors.initials: NK
authors.lastname: Mohanty
authors.forename: Sunita
authors.initials: S
authors.lastname: Saxena
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D007194:India; D008297:Male; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004272:DNA, Mitochondrial; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins