TP53 overexpression in recurrent endometrial carcinoma

Abstract Objective. To study alterations within the p53 pathway in relation to the development of recurrent stage I endometrioid endometrial carcinoma. Methods. Paraffin-embedded tumor tissue of both primary and recurrent tumors from 44 patients with and 44 without recurrence was used for immunohistochemical analysis of TP53, hMdm2, P21 Waf1/Cip1 and M30. DNA was extracted, and mutation analysis of p53 (exon 5–8, 11) was performed by direct sequencing. Results. TP53 overexpression was significantly associated with recurrent disease: Odds Ratio 3.8 (95% CI: 1.5–9.8). Overexpression of TP53 was associated with lower staining indices (SI:0–9) of both hMdm2 and P21 in tumors of patients with recurrence, compared to controls: 2.0 ± 0.4 vs. 4.0 ± 0.8 and 1.9 ± 0.8 vs. 3.6 ± 0.8, respectively. Eight p53 missense mutations were identified in six patients with recurrence and two controls. One nonsense mutation was found in a patient with recurrence and one deletion in a control patient. Only a minority of TP53 overexpression cases could be explained by the presence of these p53 mutations. Conclusion. TP53 overexpression was significantly predictive for recurrent endometrial carcinoma, and mostly not correlated with p53 mutations. Concomitant low hMdm2 and P21 Waf1/Cip1 expression in tumors with overexpressed TP53 suggests a dysfunctional TP53-P21 Waf1/Cip1 pathway.