p53MutaGene: EXAMPLES


Example 1: Schematic representation of the p63/Sharp-1 axis in the two possible scenarios of wt p53 expressing and mut-p53 expressing tumours. In wt p53 expressing tumours, p63 is fully active and is therefore able to control expression (potentially via direct binding on the promoter) of Sharp-1 expression. In mut-p53 expressing tumours p63 is sequestered and consequentially repressed by mut-p53. This results in disruption of the p63/Sharp-1 axis, which is observed in the correlation plot (panel B) as no increase in Sharp-1 expression parallels the p63 expression increase.


A,B) Correlation between p63 expression and Sharp-1 expression was computed in the two cohorts of wt p53 expressing and mut-p53 expressing breast cancers from the METABRIC dataset. A statistically significant negative shift was observed in the Pearson correlation coefficient from 0.34 to 0.03 (p value=0.003), suggesting a disruption by mut-p53 of the p63/Sharp-1 positive axis.
C,D) p53Mutagene predicts a significant effect of mut-p53 on the p63/Sharp-1 axis.


Example 2:p53Mutagene validates a significant effect of mut-p53 on NF-Y activity.

p53Mutagene validates a significant effect of mut-p53 on NF-Y activity.
A,B) Correlation between NFY-A expression and its well-established transcriptional targets was computed in the two cohorts of wt p53 expressing and mut-p53 expressing tumours. Based on the literature, the NFY-A/CDC25 correlation was computed in the breast cancer dataset Metabric, where a statistically significant positive shift from 0.03 to 0.25 was observed (p value=0.025). Similarly, the correlation between NFY-A and PDGFRB was computed in a colon carcinoma cohort (GSE39582), where a positive shift from -0.09 to 0.15 was observed (p value=0.008).


Example 3: p53Mutagene Discovery Mode identified ETS2 as an effector of mut-p53 in alteration of gene networks.

p53Mutagene Discovery Mode identified ETS2 as an effector of mut-p53 in alteration of gene networks.
A) In a gene list generated in a mut-p53 experimental setting (MDA-MB-231-shGFP or MDA-MB-231-shmut-p53) p53Mutagene Discovery Mode ranked ETS2 as the most affected TF, and indicated 9 potential targets. These targets all show a significant shift in correlation with ETS2 in mut-p53-expressing breast cancers compared to wt p53 (Metabrics dataset). TF, transcriptional factor; N, number of targets. Specific p values are indicated between brackets.
B,D) Plots depict a significant shift in correlation between ETS and ARHGAP24 (0.2 to -0.15) or EPHB2 (-0.01 to 0.32) or DIXDC1 (0.16 to -0.09) in mut-p53 expressing tumours compared to those expressing wt p53.


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