Association of glutamate carboxypeptidase II (GCPII) haplotypes with breast and prostate cancer risk

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.

► Six novel and two known variants were observed in GCPII. ► D191V variant increases breast cancer risk by affecting plasma folate. ► V108A and P160S variants reduce breast cancer risk. ► V108A and G245S associated with prostate cancer risk. ► P160S reduces breast/prostate cancer risk by high turnover of GCPII (in silico).