Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional fingerprint is a more definitive downstream indicator of p53 function. Herein, we analyzed transcript profiles of 251 p53-sequenced primary breast tumors and identified a clinically embedded 32-gene expression signature that distinguishes p53-mutant and wild-type tumors of different histologies and outperforms sequence-based assessments of p53 in predicting prognosis and therapeutic response. Moreover, the p53 signature identified a subset of aggressive tumors absent of sequence mutations in p53 yet exhibiting expression characteristics consistent with p53 deficiency because of attenuated p53 transcript levels. Our results show the primary importance of p53 functional status in predicting clinical breast cancer behavior.
Introduction Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction.
We use a mixture model, involving differentially expressed (DE) and non-DE genes, that captures the most common problem of finding DE genes. Factors determining FDR are (1) the proportion of truly differentially expressed genes, (2) the distribution of the true differences, (3) measurement variability and (4) sample size. Many current small microarray studies are plagued with large FDR, but controlling FDR alone can lead to unacceptably large FNR. In evaluating a design of a microarray study, sensitivity or FNR curves should be computed routinely together with FDR curves. Under certain assumptions, the FDR and FNR curves coincide, thus simplifying the choice of sample size for controlling the FDR and FNR jointly.
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