The timing and characterization of p53 mutations in progression from atypical ductal hyperplasia to invasive lesions in the breast cancer

The main reason for the recent interest in p53 is that almost 50% of human cancers contain P53 gene mutations. The majority of studies on p53 alterati ons in breast cancer have been limited to the isolated cases of ductal carc inoma in situ and infiltrating ductal carcinoma. The aims of this study wer e to determine the status and timing of p53 mutation in the progression fro m atypical ductal hyperplasia to invasive cancer, and to evaluate the patte rns of p53 mutations in noninvasive and invasive lesions. Available lesions of invasive (n=88) and noninvasive (n=76) lesions were microdissected in 1 07 paraffin-embedded tissues (19 ductal carcinomas in situ, 57 invasive car cinomas with intraductal components, and 31 pure invasive carcinomas) and d ouble-strand DNA sequencing was performed in exon 4-9 of the p53 gene. Amon g in situ cancers without invasive disease 36.8% had p53 mutations whereas in situ cancer with concurrent invasive disease showed p53 mutations in 33. 3% of cases. In particular, two of seven atypical ductal hyperplasias harbo red p53 alterations (one insertion and one missense mutation) in exon 8. Th e invasive component harbored p53 mutations in 30 of 88 cases (34.1 %). We also discovered a novel deletion of 14 bp in exon 6 of two invasive lesions . The invasive component (1.33+/- 0.13) carried a greater number of p53 mut ations than its counterparts (1.19+/-0.10) and demonstrated more frequent m ultiple mutations (23.3% vs. 15.4%), but without statistical significance. Moreover, no statistical significance could be attached to the mutation fre quency in the zinc-binding domains (26.7% vs. 15.4%), the directly DNA cont act region (13.3% vs. 15.4%) and the missense mutation of p53 (50.0% vs. 57 .7%) of the two groups. Based on our results, in spite of the small number of the lesions investigated, p53 mutation can occur at the stage of atypica l ductal hyperplasia. The hypermutability and the specific p53 mutations in volving the biologically functional domain (e.g., zinc binding domain or DN A contact region) have an insignificant influence on invasive progression i n the breast cancer.