Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women

Abstract

Since it is well established that inactivation of p53 is involved in pathogenesis of breast cancer, it seems to be reasonable to assume that p53 genetic polymorphism at codon 72 (p53 Arg72Pro) which affects the function of p53 might have an influence on breast cancer risk. Thus, in the present study, we have studied the association of p53 Arg72Pro polymorphism with breast cancer risk. A case–control study was conducted with 191 breast cancer patients and 218 healthy female controls. p53 Arg72Pro polymorphism was examined in their association with breast cancer risk after adjustment for the epidemiological risk factors. Relationship between p53 Arg72Pro polymorphism and clinicopathological characteristics of breast cancers was also studied. In addition, frequency of somatic p53 mutation was compared according to the genotype of p53 Arg72Pro polymorphism. p53 72Pro/Pro homozygotes showed a significant increase in the risk of estrogen receptor (ER) positive breast cancer (adjusted odds ratio (OR)=2.04, P=0.04) as compared with p53 72Arg/Arg homozygotes, whereas such an association was not found between p53 72Pro/Pro homozygotes and ER negative breast cancer risk. Subset analysis according to menopausal status showed that p53 72Pro/Pro homozygotes were significantly associated with ER positive breast cancer risk in postmenopausal women (adjusted OR=3.42, P=0.01) but not in premenopausal women. Frequency of ER positive tumors was significantly ( p<0.01) higher in breast cancer patients with p53 72Pro/Pro genotype (82.8%) than those with p53 72Arg/Arg genotype (54.5%). Mutational analysis of p53 in tumors showed that p53 72Pro/Pro homozygotes had a lower frequency of p53 mutation (3.5%) than p53 72Arg/Arg homozygotes (10.5%). It is suggested that p53 Arg72Pro polymorphism is associated with ER positive breast cancer risk, especially, in postmenopausal women. The higher frequency of p53 somatic mutation in p53 72Arg/Arg homozygotes than p53 72Pro/Pro homozygotes is consistent with the thesis that the function of p53 72Pro/Pro is impaired so that a further alteration of p53 gene is less required in p53 72Pro/Pro homozygotes than p53 72Arg/Arg homozygotes.