p53 mutation in breast cancer: about apples, oranges and unusual p53 mutations: a response to Patoc et al.
p53 mutation in breast cancer and in breast-cancer stromal cells: a strong note of caution
In december 2007, Patocs et al., published a paper describing p53 mutations in both breast tumors and breast-cancer stromal cells
Patocs, A, Zhang, L, Xu, Y, Weber, F, Caldes, T, Mutter, GL, Platzer, P, and Eng, C. “Breast-Cancer Stromal Cells With Tp53 Mutations and Nodal Metastases.” N Engl J Med 357, no. 25 (2007): 2543-51.
Inclusion and analysis of Patocs data in the UMD p53 database led to surprising observations:
i) the frequency of TP53 mutations in sporadic breast cancer is elevated (54% versus 20% in the literature).
ii), the frequency of tumors with double mutations is exceptionally high (23% versus 1-2%).
iii, several mutations have never been described in any study i.e. the P89S mutant identified in 21 samples in the Patocs's study has never been reported among the 3000 sporadic and familial breast carcinoma included in the UMD-p53 database or any other database.
iv) the distribution of p53 mutant loss of activity is clearly out of range compared to former studies of breast carcinoma (see figure). This distribution is similar to others studies well know to contain artefactual data
v) few mutations at hot spot codons
These features are not specific for breast-cancer stromal cells but are also found in breast tumors indicating that Patocs et al., data can be compared to any mutation database despite their claims.
Figure: Meta-analysis of p53 mutant loss of function in breast tumors. For each publication, the mean and 95% CI of p53 mutant residual activity is graphically displayed. Points, mean p53 activity as measured by transactivation with the WAF1 promoter; bars, 95 % CI. The mean and 95 % CI of p53 activity for all studies in the database or for the 3000 breast cancers is shown on the far left of the graph. Horizontal line, mean of the combined studies. The publication code is indicated on the x-axis : the first number is an anonymous ID for the publication and the second number indicates the number of p53 mutants included in this study. The y-axis corresponds to p53 transactivation activity (100% for wt p53).
All mutations of the Patocs’s study (ref 2336, red), have been analyzed together (2336-158) or divided in stromal (2336s-74) or tumor (2336t-84) cells to verify if the data were specific to a particular cellular compartment. The majority of mutant p53 described by Patocs et al, display a significant biological activity, a feature not found in mutant p53 described in other studies.
Data from publications 1266 and 2125 (green) are well know to be due to sequencing errors.
Data from reference 485 can be used as a reference as p53 mutations was analyzed by sequencing both DNA and RNA in two different samples in two independant studies.
Williams, C., Norberg, T., Ahmadian, A., Ponten, F., Bergh, J., Inganas, M. et al. (1998). Assessment of sequence-based p53 gene analysis in human breast cancer: messenger RNA in comparison with genomic DNA targets. Clin Chem, 44(3), 455-462.
see this page for more information about these statistical analysis
Results of Patocs et al. have been challenged by different groups:
Zalcman, G., Bergot, E., & Hainaut, P. (2008). Breast-cancer stromal cells with TP53 mutations. N Engl J Med, 358(15), 1635-6; author reply 1636.
Soussi-Zander C & Soussi T. (2008). Breast-cancer stromal cells with TP53 mutations. N Engl J Med, 358(15), 1635; author reply 1636.
Roukos, D. H. (2008). Breast-cancer stromal cells with TP53 mutations. N Engl J Med, 358(15), 1636; author reply 1636.
Campbell, I. G., Qiu, W., Polyak, K., & Haviv, I. (2008). Breast-cancer stromal cells with TP53 mutations. N Engl J Med, 358(15), 1634-5; author reply 1636.
These observations indicates that using an uncurated p53 database can lead to serious biais. Work of Patocs et al., is not included in the curated UMD p53 database.
The UMD p53 database is protected by the European Union Council Directive N° 96/9/EC, OJ (L77) 20 (1996). Extracting, copying or reuse of data from databases without permission are covered by this directive