title: Association of glutamate carboxypeptidase II (GCPII) haplotypes with breast and prostate cancer risk.
abstract: In view of the pivotal role of glutamate carboxypeptidase II (GCPII) in carcinogenesis, its expression as prostate specific membrane antigen (PSMA) and folate hydrolase (FOLH1) may be influenced by its haplotypes, contributing to the etiology of prostate and breast cancer. To test this hypothesis, breast and prostate cancer cases and controls were subjected to whole gene screening of GCPII and correlated with plasma folate levels and PSMA expression. The impact of variants on a 3-dimensional structure of GCPII was explored by in silico studies. Six novel variations i.e. V108A, P160S, Y176H, D191V, G206R and G245S; and two known variations i.e. R190W and H475Y were identified in GCPII. All-wild haplotype and a haplotype harbouring D191V showed association with breast cancer risk while haplotypes harbouring V108A and P160S reduced the risk. Haplotypes with V108A and G245S variants showed increased risk for prostate cancer due to high PSMA expression while P160S conferred protection against prostate cancer. In silico studies suggests that P160S and R190W variants result in relaxed substrate binding facilitating either rapid catalysis or exchange of substrates and products in the active site which was substantiated by high plasma folate levels associated with these variants. On the contrary, D191V was associated with very low plasma folate levels despite having a high PSMA expression. This is the first comprehensive study examining variations in GCPII in relation to breast and prostate cancer risk. Changes in the plasma folate levels and changes in PSMA expression are associated with breast and prostate cancer risk respectively.
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, India.
authors.forename: Shree
authors.initials: S
authors.lastname: Divyya
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.forename: Anthony
authors.initials: A
authors.lastname: Addlagatta
authors.forename: P V L N
authors.initials: PV
authors.lastname: Murthy
authors.forename: Ch Ram
authors.initials: ChR
authors.lastname: Reddy
authors.forename: Raghunadha Rao
authors.initials: RR
authors.lastname: Digumarti
authors.forename: Suryanarayana Raju
authors.initials: SR
authors.lastname: Gottumukkala
authors.forename: Sreedhar Amere
authors.initials: SA
authors.lastname: Subbarao
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood; D015972:Gene Expression Regulation, Neoplastic; D043425:Glutamate Carboxypeptidase II / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics*; D011487:Protein Conformation; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D005492:Folic Acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II