Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

Agata Sikorska,Alexander Kind,Marek Switonski,Krzysztof Flisikowski,Angelika Schnieke,Tatiana Flisikowska,Monika Stachowiak

doi:10.1007/s13353-018-0461-6

Abstract

Familial adenomatous polyposis (FAP) is a hereditary predisposition to formation of colon polyps that can progress to colorectal cancer (CRC). The severity of polyposis varies substantially within families bearing the same germline mutation in the adenomatous polyposis coli (APC) tumour suppressor gene. The progressive step-wise accumulation of genetic events in tumour suppressor genes and oncogenes leads to oncogenic transformation, with driver alterations in the tumour protein p53 (TP53) gene playing a key role in advanced stage CRC. We analysed groups of pigs carrying a truncating mutation in APC (APC1311/+; orthologous to human APC1309/+) to study the influence of TP53 polymorphisms and expression on the frequency of polyp formation and polyp progression in early-stage FAP. Five generations of APC1311/+ pigs were examined by colonoscopy for polyposis severity and development. A total of 19 polymorphisms were found in 5′-flanking, coding, and 3′ untranslated regions of TP53. The distribution of TP53 genotypes did not differ between APC1311/+ pigs with low (LP) and high (HP) number of colon polyps. p53 mRNA expression was analysed in distally located normal mucosa samples of wild-type pigs, APC1311/+ LP and HP pigs, and also in distally located polyp samples histologically classified as low-grade (LG-IEN) and high-grade intraepithelial dysplastic (HG-IEN) from APC1311/+ pigs. p53 mRNA expression was found to be significantly elevated in HG-IEN compared to LG-IEN samples (p = 0.012), suggesting a role for p53 in the early precancerous stages of polyp development.

Highlights

Colorectal cancer (CRC) is the third most common cancer worldwide (Arnold et al 2017)
The progressive step-wise accumulation of genetic events in tumour suppressor genes and oncogenes leads to oncogenic transformation, with driver alterations in the tumour protein p53 (TP53) gene playing a key role in advanced stage colorectal cancer (CRC)
The distribution of TP53 genotypes did not differ between APC1311/+ pigs with low (LP) and high (HP) number of colon polyps. p53 mRNA expression was analysed in distally located normal mucosa samples of wild-type pigs, APC1311/+ LP and HP pigs, and in distally located polyp samples histologically classified as low-grade (LG-IEN) and high-grade intraepithelial dysplastic (HG-IEN) from APC1311/+ pigs. p53 mRNA expression was found to be significantly elevated in HG-IEN compared to LG-IEN samples (p = 0.012), suggesting a role for p53 in the early precancerous stages of polyp development

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide (Arnold et al 2017). We previously generated a line of genetically modified pigs (German Landrace x Pietrain crossbred) carrying an APC1311 mutation (orthologous to human APC1309) to model human FAP (Flisikowska et al 2012). Several generations of APC1311/+ animals have been examined, revealing that. J Appl Genetics (2018) 59:485–491 porcine polyps spread throughout colon and rectum, closely resemble those in early stage human FAP by localisation, anatomical, morphological, histological and molecular criteria (Flisikowska et al 2017; Stachowiak et al 2017). It is apparent that different pigs with the same mutation can exhibit very different numbers of polyps, classified as low (LP) or high (HP) polyp animals

Methods

Results

Conclusion