Base Excision Repair Gene Mutations and Polymorphisms as a Potential Modifier of Breast Cancer Risk

摘要

Our hypothesis is that functional redundancy in Base Excision repair (BER) may permit polymorphism to accumulate in these parallel pathways. Deficiencies in BER may lead to elevated spontaneous mutation rates and an earlier onset of cancer. We have analysed two BER enzymes: TDG and MEDl(MBD4), both DNA N-glycosylases that remove the T residue in a T/U mismatch and the U residue in a U/U mismatch. Our analysis revealed that neither MED1 nor TDG polymorphisms appear to be related to breast cancer of the general population. Curiously, compounded heterozygous exon 5 and exon 10 polymorphisms of the TDG gene, in our analysis of 590 patients is under-represented. It may imply that the TDG gene has a second role in humans besides DNA repair, and that the presence of both alleles in a person may lead to embryonic lethality. The latter can be a checkpoint for eliminating defective gene coding for defective enzymes that may be damaging later in life. We observed that the exon 10 polymorphism of TDG is unusually high in frequency in the high risk ovarian population. This potentially important finding needs further examination with a larger population in the future.