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.