p53 mutations and expression in breast carcinoma in situ

The p53 tumor suppressor gene is altered in approximately half of human can cers. Although p53 mutations are common in invasive breast carcinoma, few h ave been identified in breast carcinoma in situ (intraductal breast carcino mas). Most studies of p53 in breast carcinoma in situ are immunohistochemic al studies of p53 staining in paraffin-embedded tissue sections. Few studie s have isolated the tumor cells and subjected them to DNA sequence analysis . The current study was undertaken to characterize p53 in a cohort of breas t carcinoma in situ cases, both with and without invasive disease. Fifty-ei ght frozen breast biopsy samples were used for these investigations, Twenty -seven cases had only ductal carcinoma in situ (CIS) and 31 cases had evide nce of both invasive and in situ carcinoma, DNA. sequence alterations in ex ons 2 through 11 of p53 were screened by the single-strand conformational p olymorphism technique. Exons with altered mobility were sequenced, Among br east CIS cases without invasive disease, 22% had p53 mutations and 7% had D NA sequence alterations of unknown significance. Analysis of breast CIS wit h concurrent invasive disease demonstrated p53 mutations in 19% of cases an d one (3%) DNA alteration of unknown significance. Each carcinoma having a p53 mutation in the breast CIS component had the identical mutation in the invasive component of the same tumor indicating a clonal relationship betwe en the two tumor components. p53 protein overexpression was identified in 2 2% of pure intraductal breast carcinomas and in 35% of breast CIS with inva sive disease. Comparison of immunostaining and DNA sequence alterations sho wed a significant association between overexpression and mutations (P = 0.0 037) in cases of CIS without invasion, and similarly between overexpression and mutations in cases of CIS with invasion (P = 0.007), p53 mutations and p53 overexpression were relatively common in intraductal breast carcinomas but were not observed in adjacent normal breast lobules or ducts in 9 case s available for DNA analysis. The frequency of p53 alterations when compari ng breast CIS with and without an invasive component indicated that p53 mut ations usually occur before invasion during the progression of breast cance r, as is observed for a number of other adult solid tumors.