Reference SummaryMollersen L, Mutat Res 2004 Jan 10;557(1):29-40

Title

Adenomatous polyposis coli truncation mutations in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced intestinal tumours of multiple intestinal neoplasia mice.

Authors

Mollersen L; Vikse R; Andreassen A; Steffensen IL; Mikalsen A; Paulsen JE; Alexander J

Journal

Mutat Res

Volume

557

Issue

1

Year

2004

Pages

29-40

Abstract

The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces intestinal tumours in C57BL/6J-multiple intestinal neoplasia (Min)/+ mice. The main mechanism for PhIP-induced tumour induction in Min/+ mice is loss of the wild-type adenomatous polyposis coli (Apc) allele, i.e. loss of heterozygosity (LOH). In this study, single injections of either 10, 17.5 or 25mg/kg PhIP on days 3-6 after birth all increased the mean number of small intestinal tumours two to three-fold, from 37.7 in controls to 124.8 in the PhIP-treated Min/+ mice. In total, we analysed 292 small intestinal tumours and 253 of these had LOH. The frequency of LOH in the Apc gene was 88, 93, 83 and 84% in tumours of 0, 10, 17.5 and 25mg/kg PhIP-treated mice, respectively. Therefore, these lower doses of PhIP did not reduce the frequency of LOH, as found in our previous study with a single injection of 50mg/kg PhIP (Mutat. Res. 1-2 (2002) 157). In the second part of this study, we wanted to characterise Apc truncation mutations from tumour samples apparently retaining the Apc wild-type allele from this and two previous experiments with PhIP-exposed Min/+ mice. In the first half of exon 15 in Apc, we verified 25 mutations from 804 tumour samples of PhIP-treated mice. Of these were 60% G-->T transversions, and 16% G deletions, indicating that these are the predominant types of PhIP-induced truncation mutations in the Apc gene in Min/+ mice. Most of the mutations were located between codon 989 and 1156 corresponding to the first part of the beta-catenin binding region. We also identified two Apc truncation mutations from 606 spontaneously formed intestinal tumours from untreated Min/+ mice, one C-->T transition and one T insertion, which were different from those induced by PhIP.

Links

J:87470 – Mouse Genome Informatics
14706516 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

52

C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon tumor
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
Intestine - Large Intestine - Colon

80 - 92

C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor Intestine - Small Intestine

observed - 100

C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
Intestine - Small Intestine

observed - 100