S01 A genetic interval confers protection from colitis and colitis-associated cancer in a model of bacteria-induced colon cancer

Abstract

Background: Inflammatory bowel disease, especially ulcerative colitis, is linked to an elevated risk to develop colon cancer. Although it is well known from GWAS that genetic predisposition plays a role in the etiology of colitis, genes involved in the development of colitis-associated colorectal cancer (caCRC) are not well defined. Aim: The aim of this study is to examine genetic factors that determine susceptibility to chronic colitis and caCRC. Different mouse models identified the telomeric region of chromosome 3 to be involved in colitis susceptibility. We aimed to further dissect this region and asked if it could be involved in the development of caCRC. Material and Methods: We used an innate mouse model (RAG-/-) where infection with Helicobacter hepaticus leads to colitis and splenomegaly in the susceptible mouse strain 129S6 but not in mice harboring a chromosome 3 interval of C57Bl/6 mice (C3B). The susceptibility interval was dissected by microsatellite and SNP genotyping using congenic lines. We also generated reciprocal bone marrow chimeras by reconstituting lethally irradiated 129.RAG and 129.C3B.RAG mice with bone marrow from the opposite strain, prior to H. hepaticus infection. To accelerate caCRC we infected with H. hepaticus followed by injection of the carcinogen 2-azoxymethane (AOM). Results: Different recombinants enabled us to narrow down the susceptibility region to a locus of 1.7Mb. Recombinants containing part of the C3B region were not only protected from colitis but also from caCRC. Resistance is conferred by the haematopoietic compartment as mice receiving bone-marrow harboring the recombined C3B locus were protected. Conclusions: We characterized a colitis and caCRC susceptibility interval acting in bone-marrow derived cells, which is a potential candidate for further investigation in human disease.