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Contribution of allelic imbalance to colorectal cancer

ABSTRACT: Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge, and unbiased CRISPR-Cas9 knockout and activation screens identified altogether 79 genes within AI peaks regulating cell growth. Genetic and functional data implicates loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.

PROVIDER: EGAS00001002966 | EGA |

REPOSITORIES: EGA

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Project description:Kim2007 - Crosstalk between Wnt and ERK pathways Experimental studies have shown that both Wnt and the MAPK pathways are involved in the pathogenesis of various kinds of cancers (eg. colorectal cancer). The crosstalk between the two pathways have also been identified. Here, Kim et al., (2007) have integrated the experimental evidences on crosstalk mechanisms between the two pathways into a pathway model, and have identified the existence of a hidden positive feedback loop and suggest that this positive feedback loop might participate in the pathogenesis of colorectal cancer. This model is described in the article: A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways. Kim D, Rath O, Kolch W, Cho KH. Oncogene 2007 Jul; 26(31): 4571-4579 Abstract: The Wnt and the extracellular signal regulated-kinase (ERK) pathways are both involved in the pathogenesis of various kinds of cancers. Recently, the existence of crosstalk between Wnt and ERK pathways was reported. Gathering all reported results, we have discovered a positive feedback loop embedded in the crosstalk between the Wnt and ERK pathways. We have developed a plausible model that represents the role of this hidden positive feedback loop in the Wnt/ERK pathway crosstalk based on the integration of experimental reports and employing established basic mathematical models of each pathway. Our analysis shows that the positive feedback loop can generate bistability in both the Wnt and ERK signaling pathways, and this prediction was further validated by experiments. In particular, using the commonly accepted assumption that mutations in signaling proteins contribute to cancerogenesis, we have found two conditions through which mutations could evoke an irreversible response leading to a sustained activation of both pathways. One condition is enhanced production of beta-catenin, the other is a reduction of the velocity of MAP kinase phosphatase(s). This enables that high activities of Wnt and ERK pathways are maintained even without a persistent extracellular signal. Thus, our study adds a novel aspect to the molecular mechanisms of carcinogenesis by showing that mutational changes in individual proteins can cause fundamental functional changes well beyond the pathway they function in by a positive feedback loop embedded in crosstalk. Thus, crosstalk between signaling pathways provides a vehicle through which mutations of individual components can affect properties of the system at a larger scale. Figure 6 of the reference publication has been reproduced. The model as such reproduces the plots corresponding to the normal conditions. To obtain simulations under 1) beta-cataenin mutation; set V12=0.846 (two-fold of the beta-catenin synthetic rate than the normal system. i.e. 2*0.426), 2) PP2A mutation; set Vmax4=Vmax5=33.75 (three-fourths of the PP2A activity that the normal system. i.e. (3/4)*45). The simulation was performed using Copasi 4.10 (Build 55). This model is hosted on BioModels Database and identified by: BIOMD0000000149 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Contribution of allelic imbalance to colorectal cancer

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