Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation.

Boulard O., Kirchberger S., Royston DJ., Maloy KJ., Powrie FM.

Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus-induced colitis and associated cancer susceptibility in a 129.RAG(-/-) mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1(+) innate lymphoid cells. Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

DOI

10.1084/jem.20120239

Type

Journal article

Journal

J exp med

Publication Date

02/07/2012

Volume

209

Pages

1309 - 1324

Keywords

Animals, Azoxymethane, Carcinogens, Chromosome Mapping, Chromosomes, Mammalian, Colitis, Colorectal Neoplasms, Disease Resistance, Genetic Loci, Genetic Predisposition to Disease, Helicobacter Infections, Helicobacter hepaticus, Host-Pathogen Interactions, Humans, Immunity, Innate, Inflammation, Mice, Mice, 129 Strain, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, Telomere

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