TP53 mutation is an early event in breast cancer progression.

Abstract

Abstract Abstract #1047 Background: In breast cancer, previous studies have shown that somatic TP53 mutations cause a more aggressive disease with poor clinical outcome and may impact treatment response. Although TP53 mutation is considered to be an early event in breast cancer, the timing of TP53 mutations is not known, and there are controversies regarding the cellular origin and linear model of breast cancer. The purpose of this study was to investigate whether TP53 mutations are early events in breast cancer progression.
 Methods: From a population-based cohort of women diagnosed between 1986 and 2004 either with a pure ductal carcinoma in situ (DCIS), a pure invasive cancer (<15mm) or a mixed lesion (i.e. invasive cancer with a DCIS component), we included 118 women with stored frozen tissue. Mixed lesions were microdissected using LCM (laser capture microdissection) on a PALM slide to separate in situ and invasive tumor cells. DNA was isolated using phenol-chloroform extraction. The entire coding sequence of TP53 was analyzed for mutations by direct sequencing on a 3730 DNA analyzer.
 Results: Of 118 tumor samples, 19 were detected with a TP53 mutation; five 5 of 32 (15.6%) pure DCIS, 4 of 38 (10.5%) pure invasive cancers and 10 of 48 (20.8%) mixed lesions. In the mixed lesions, both the invasive and the DCIS component showed the same mutation in all 5 cases where we successfully could microdissect the two components separately. Pure DCIS demonstrated missense mutations (4/5, 80%) more frequently than pure invasive cancers (2/4, 50%) and mixed lesions (4/10, 40%), although this difference was not statistically significant (p=0.3). Also, the frequency of missense mutations in the DNA binding domain was not statistically different between the three groups.
 Conclusion: TP53 mutation is likely an early event in breast cancer, occurring previous to or in the in situ stage. Presence of the same mutation in both DCIS and invasive component from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression into invasive cancer is less clear and may vary between subtypes of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1047.