TP53/p53 alterations and Aurora A expression in progressor and non-progressor colectomies from patients with longstanding ulcerative colitis

Abstract

Aneuploidy is a common feature in the colonic mucosa of patients suffering from the inflammatory bowel disease ulcerative colitis (UC) and often precedes the development of dysplasia and cancer. Aneuploidy is assumed to be caused by missegregation of chromosomes during mitosis, often due to a faulty spindle assembly checkpoint. p53 is a tumour suppressor protein known to regulate the spindle assembly checkpoint and is frequently mutated in aneuploid cells. Aurora A is a presumed oncoprotein, also involved in regulation of the spindle assembly checkpoint. In the present study, we examined the mutational frequency of TP53 and the protein levels of p53 in a set of 20 progressor and 10 non-progressor colectomies from patients suffering from longstanding UC. In addition, we re-examined previously published immunohistochemical data on Aurora A expression using the same material. Levels of Aurora A were re-examined with regard to DNA ploidy status and dysplasia within the progressors, as well as in relation to p53 accumulation and TP53 mutational status. We detected p53 accumulation only within the progressor colectomies, where it could be followed back 14 years prior to the colectomies, in pre-colectomy biopsies. TP53 mutations were detected in both progressors and non-progressors. Expression levels of Aurora A were similar in the progressors and non-progressors. Within the group of progressors however, low levels of Aurora A were associated with areas of DNA aneuploidy, as well as with increasing degrees of dysplasia. Our results indicate that alterations in p53 may be an early biomarker of a progressor colon, and that p53 is accumulated early in UC-related carcinogenesis. Furthermore, a decreased Aurora A expression is associated with the development of DNA aneuploidy, as well as with dysplasia in UC progressors.

Figure 1

Immunohistochemical staining of (A) Aurora A and (B) p53 in dysplastic ulcerative colitis (UC) colonic mucosa. Aurora A staining of non-dysplastic UC mucosa and non-UC control has been previously presented (35). p53 staining illustrates heterogeneity, showing one positive and one negative crypt. Images are shown at ×400 magnification.

Figure 2

Aurora A expression and DNA ploidy status. Levels of Aurora A expression in ulcerative colitis non-progressors (all diploid) and in the diploid and aneuploid lesions from progressors. Within the progressors: lesions harbouring aneuploid populations had significantly decreased levels of Aurora A expression compared to diploid lesions (P=0.020). Median values with 95% confidence interval.

Figure 3

Aurora A expression in progressor ulcerative colitis (UC) colons with and without adenocarcinoma. Levels of Aurora A protein expression in lesions from (A) 10 non-progressor colons (white circle) and levels of Aurora A with increasing degrees of dysplasia within the 20 progressor colons, including those harbouring adenocarcinomas, and (B) the decreasing levels of Aurora A with increasing degrees of dysplasia in the 14 progressor colons remaining when excluding the colons harbouring adenocarcinomas (high- and low-grade dysplasia are combined in statistical analysis) (p=0.025). The asterisk (*) indicates statistical significance at a p-value of <0.05, and the horizontal bar indicates overall difference between groups [as detected by the linear mixed model (LMM) with Bonferroni post-hoc test]. Median values with 95% confidence interval are shown.

Figure 4

Aurora A expression and p53 accumulation. Aurora A expression in ulcerative colitis (UC)-progressor colons with lesions positive for p53 accumulation (>5% positivity) and in progressor colons without any lesions displaying p53 accumulation. Note the decreased expression of Aurora A in progressors without p53 accumulation, although not to a statistically significant degree when inter-patient differences were accounted for. Median values with 95% confidence interval are shown.