NGFN-PLUS

Small intestine cancer

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Coordinator:    Prof. Dr. Bernhard G. Herrmann
Institution: Max-Planck-Institut für molekulare Genetik
Homepage: http://www.molgen.mpg.de

Key genetic alterations occuring during colon cancer initiation and progression are well-known: for instance, deregulation of Wnt/beta-catenin signalling (often by mutation of APC), activating mutations in KRAS, and mutations that affect p53, the TGF-beta and PI-3K pathways are common events. In addition to these tumor-specific, somatic alterations, the individual genetic background is known to have a major effect on the life-time risk of developing cancer, and on cancer progression. The genetics of cancer susceptibility are however complex (polygenic), and thus it is almost impossible to assess the influence of individual factors in the genetic background of humans on the lifetime risk of developing this disease.
Mice share 99% of genes with humans, and also share common diseases. In particular, similar mutations cause colon cancer in mice and humans, and mouse models of human colon carcinogenesis are available (for instance APC-Min mice, which harbour a mutation in the APC gene, that is also prominently mutated in a majority of human colon cancer cases) Furthermore it is known that the genetic background of mice influences tumor multiplicity and the spectrum of organs affected. Due to new genetic tools, mice have become the prominent model organism to decipher complex traits.
This Integrated Genome Network seeks to unravel key genetic modifiers of colon cancer initiation and progression. Our work is based on the availability of two powerful new tools for genetic analysis, chromosome substitution strains (CSS) of the mouse and ultrahigh-throughput sequencing (Solexa), allowing us to enter a new dimension of the genetic analysis of cancer. Our focus is on modifiers, which globally affect the epigenetic control and gene activity of many genes. Human tumor material is analysed in parallel to allow translation of knowledge obtained in the mouse model to clinical application in the future. The isolation of multiple genetic traits affecting cancer initiation, progression and recurrencewill allow to define low- and high-risk groups among patients, and adapt treatment and follow-up regimes accordingly.

Latest results can be found in detail in the descriptions of the subprojects

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