Expression signatures of TP53 mutations in serous ovarian cancers

Abstract

Background: Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease.

Methods: The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage.

Results: Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers.

Conclusions: This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.

Figure 1

Hierarchical clustering by both probes and samples. A) All 89 cancers from the study were clustered using the 9 probes derived from a global T test of differential expression between mutant and wild type cancers. Actual p53 status is indicated on the bar below the heatmap (mutant = red and wild type = blue). Red indicates high level expression. B) The 40 early stage cancers were clustered by binary p53 status using the top 42 probe sets. Actual p53 status is indicated in the bar below the heatmap (mutant = red and wild type = blue).

Figure 2

Class prediction of binary p53 mutation status in advanced cancers using the algorithm derived from the binary status of early stage cancers. The X axis is a measure of the confidence of the predictor for class assignment. Four mutant and three wild type tumors were mis-predicted. True mutational status is indicated by the symbols.