A systematic review of genetic polymorphisms and breast cancer risk

Studies investigating the relationship between common genetic variants and cancer risk are being reported with rapidly increasing frequency. We have i dentified 46 published case-control studies that have examined the effect o f common alleles of 18 different genes on breast cancer risk. Of these, 12 report statistically significant associations, none of which were reported by more than one study, However, many of the studies were small: 10 of the 46 had 80% power or greater to detect a rare allele homozygote relative ris k <2.5, We therefore combined the results of individual studies to obtain m ore precise estimates of risk. Statistically significant differences in gen otype frequencies were found in three case-control comparisons of unselecte d cases. These were for CYP19 (TTTA)(n) polymorphism [(TTTA)(10) carrier od ds ratio (OR) = 2.33; P = 0.002], the GSTP1 Ile105Val polymorphism (Val car rier OR = 1.60; P = 0.02), and the TP53 Arg72Pro polymorphism (Pro carrier OR = 1.27; P = 0.03), In addition, the GSTM1 gene deletion was found to be significantly associated,vith postmenopausal breast cancer (null homozygote OR = 1.33; P = 0.04), There was also some evidence that homozygotes for th e PR PROGINS allele are protected against breast cancer, although this resu lt was of borderline statistical significance. For polymorphisms in BRCA1, COMT, CYP17, CYP1A1, NAT1, and NAT2, the best estimate of risk either from the individual studies or the meta-analyses was sufficiently precise to exc lude a relative risk of 1.5 or greater. For the polymorphisms in EDH17B2, E R, CYP2D6, CYP2E1, GSTT1, HSP70, and TNF alpha, the risk estimates, althoug h nonsignificant, were insufficiently precise to exclude a moderate risk (> 1.5). Precise estimation of the risks associated with these and other as ye t untested genes, as well as investigation of more complex risks arising fr om gene-gene and gene-environment interactions, will require much larger st udies.