p53 protein accumulation and mutations in normal and benign breast tissue

Mutations in the p53 gene are amongst the most common molecular changes det ected in breast cancer, and there are several reports suggesting that chang es in p53 may contribute to the pathogenesis of this disease. In a previous case-control study, we demonstrated that p53 protein accumulation detected by immunohistochemistry in normal or benign breast tissue was associated w ith a 2.5-fold increase in the risk of subsequent breast cancer, In this st udy, we investigated whether p53 gene mutations were present in the 29 p53 immunopositive normal or benign breast tissue samples and in 15 p53 immunon egative normal or benign breast tissue samples selected randomly from the o riginal study, DNA was extracted from paraffin sections and underwent PCR-S SCP analysis for exons 4 to 10, PCR products that showed abnormal mobility were excised and sequenced. Sixteen (59.2%) of the 27 immunopositive breast tissue samples and 4 (26.756) of the 15 immunonegative samples had p53 seq uence changes. There was no obvious association between the occurrence of t hese alterations and any specific histopathologic features. Ten cases showe d p53 mutations, and they were all missense base substitutions of the trans ition type. Thirteen other gene changes occurred in I I breast tissue sampl es and consisted of 8 silent (no amino acid change), 4 intronic alterations , and I indeterminate alteration. One individual had both a mutation and a silent change. In summary, p53 gene alterations can occur in normal or beni gn breast tissue, but resolution of their role in the pathogenesis of breas t cancer will require long-term follow-up studies involving comparisons of breast cancer occurrence in patients with and without p53 mutations as well as functional assays to determine their significance. Int. I. Cancer 87:73 -78, 2000, (C) 2000 Wiley-Liss, Inc.