ABSTRACT
Folate and methionine play a crucial role in DNA synthesis, repair and the epigenetic profile of cell. Hence, the alterations in the folate metabolism can lead to aberrant proliferation leading to neoplasia. Most of the studies have associated polymorphisms in methylene tetrahydrofolate reductase [MTHFR] and methionine synthase reductase [MTRR] genes with reduced risk of cervical and colorectal cancer. However, the association with breast cancer is still controversial. Further, the ivolvement of Glutamate carboxypeptidase II [GCPII] polymorphism in cancer is not known. In the present study, we analyzed if the individual and combined effects of polymorphisms in folate pathway genes viz., MTHFR 677C> T, MTHFR 1298A> C, MTRR 66A> G and GCP II 1561 C>T, have any role in altering the susceptibility to breast cancer. The DNA of 35 female breast cancer patients and 33 healthy individuals, in the Kashmiri population from India, were analyzed using a PCR-RFLP approach for the above mentioned polymorphisms. Individuals carrying the MTHFR 677CT/TT and GCPII 1561 CT genotype showed a 3.5 [95% CI: 3.1-3.7, P<0.02] and 7.7 [95% CI: 6.7-9.1, P<0.001] fold decreased risk for breast cancer than the wild types [MTHFR 677CC and GCPII 1561 CC]. Subjects with MTRR 66 G-allele showed a 4.5 fold decreased risk [OR: 0.22, 95% CI: 0.20, 0.24, P<0.0005] compared to the wild type [MTRR 66A]. Further, subjects with combined polymorphisms in MTHFR, GCPII and MTRR loci revealed a significant reduction of breast cancer risk. This study indicates [i] a protective role of polymorphisms in MTHFR, GCPII, MTRR against breast cancer in the study subjects, and [ii] combined effect of polymorphisms is more pronounced than single genetic polymorphism, thereby emphasizing the role of gene-gene interaction in the susceptibility to breast cancer