Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers

Abstract

Abstract. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, ΔNp73, ΔN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, ΔNp73 and ΔN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences ‰ (tumornormal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/ SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers. IntroductionThe p53 gene family consists of p53, p63 and p73. p73 shares substantial homology with p53. In response to DNA damage or deregulated oncogenes, full-length p73 can activate many p53 target genes, thereby inducing cell cycle arrest or apoptosis (1-7). In mice, recent genetic evidence found some support for a helper tumor suppressor role of p73 once p53 is impaired. While p73-/-mice completely lack a cancer phenotype (8), double heterozygous p53+/-, p73+/-mice have a higher tumor burden compared to p53+/-mice (9). In human cancers, however, p73 is not a classical tumor suppressor. The virtual absence of p73 inactivating mutations (10), combined with tumor-associated overexpression of wild-type p73 isoforms including TAp73 in human cancers are in sharp contrast to the notion of a tumor suppressor function. One explanation lies in the fact that, unlike p53, the p73 gene gives rise to multiple isoforms with different and often opposing functions ( Fig. 2A). Whereas the full-length isoform TAp73 largely mimics p53 function, four additional NH 2 -terminally truncated isoforms, ΔNp73, ΔN'p73, Ex2p73 and Ex23p73, act as dominant negative inhibitors of both TAp73 and wild-type p53 (11-13). The isoforms TAp73, ΔN'p73, Ex2p73 and Ex2/ 3p73 are all generated from P1 promoter-derived transcripts via alternative exon splicing (14-...

Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer

“…Recent data appear to suggest a prognostic relevance for p73 expression in EOC [172,173]. For instance, Nivazi et al [172] found a significant correlation between high-p73 expression and poor survival in patients with this malignancy.…”

TP63 and TP73 in cancer, an unresolved “family” puzzle of complexity, redundancy and hierarchy

“…More importantly, DN‐p73 is overexpressed in several tumors, among them breast [152], ovary [158,159], prostate cancers [160], melanoma [161], neuroblastoma [162] and hepatocellular carcinoma [163,164] and in most cases, DN‐p73 expression is associated with therapy failure, chemoresistance, metastasis and vascular invasion [165]. In melanoma xenografts DNp73 expression is associated with upregulation of Slug, downregulation of the actin binding protein EPLIN, activation of the IGF1R‐AKT/STAT3 pathway, loss of E‐cadherin and a higher ability to invade and metastasize [166].…”

Prognostic Impact of ΔTAp73 Isoform Levels and Their Target Genes in Colon Cancer Patients

“…Several studies have reported the expression status of TP73 isoforms in human tumors (18)(19)(20)(21)(22), but only a few showed the involvement of DTAp73 isoforms in the prognosis of patients (23)(24)(25)(26)(27)(28)(29)(30)(31). The failure or lack of tumor response is mainly due to drug resistance mechanisms.…”