SYSCOL

Systems Biology of Colorectal Cancer

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 Obiettivo del progetto (Objective)

'Colorectal cancer (CRC) is one of the most common cancers in both males and females, and it is perhaps the best understood of all epithelial tumors in terms of its molecular origin. Yet, despite large amount of work that has concentrated on understanding of colon tumorigenesis, we still do not know the full complement of molecular lesions that are individually necessary – and together sufficient – to cause colorectal cancer. Neither do we understand why some specific mutations that are relatively rare in other tumors (e.g. loss of the APC tumor suppressor) are extremely common in colorectal cancer. We propose here to use the tools of systems biology to develop a quantitative and comprehensive model of colorectal tumorigenesis. The model will include a “wiring diagram” that identifies cell-type specific and oncogenic pathways that contribute to colon tumorigenesis, and explains in molecular detail how a genotype of an individual CRC leads to activation of downstream genes that drive uncontrolled cell growth. This model will subsequently be used to find novel therapeutic targets, to guide genetic screening to identify individuals with elevated risk for developing CRC, and to classify patients into molecular subgroups to select the treatment combination which is optimal for each patient (personalized medicine). The specific objectives of the SYSCOL project are: 1. Identify genetic markers for individual risk using genotyping and sequencing of germline DNA from sporadic and familial CRC cases and controls 2. Identify genes and regulatory elements that contribute to colorectal cancer cell growth 3. Use data from Aims 1-2 to develop a quantitative model for colorectal tumorigenesis 4. Apply the model for identification of high-risk individuals, for molecular classification of the disease, and for identification of novel molecular treatment targets'

Introduzione (Teaser)

Colorectal cancer (CRC) is one of the most commonly occurring cancers. At present, there are no effective screening programmes or therapies available.

Descrizione progetto (Article)

CRC has a high prevalence in both males and females, and it is perhaps the best understood of all epithelial tumours in terms of its molecular origin. Yet, the full complement of molecular lesions necessary and sufficient to cause CRC is poorly understood.

The goal of the EU-funded 'Systems biology of colorectal cancer' (http://syscol-project.eu (SYSCOL)) project is to develop methods and tools that lead to a better understanding of the gene regulatory systems underlying the disease. The experimental part of the study entails generation of DNA and RNA sequence data from patient samples and epigenetic modification analysis. Collectively, this work aims to identify mutations and polymorphisms that affect cancer risk and delineate the mechanisms that drive CRC formation.

Project studies, so far, have led to the identification of five novel variants that increase an individual's risk of developing CRC. Three of the variants are common, but have only a small effect on risk. Two variants are rare, but individuals carrying them have a high risk of developing CRC, and early detection by screening would be of great importance for identifying high-risk patients.

The collaborative work also resulted in the discovery of an important gene switch that promotes CRC. This genetic variant is very common and therefore accounts for more inherited cancer than any other currently known genetic variant or mutation.

Another important advance was the development of an approach for detecting cancer DNA in the blood. The use of such a non-invasive method to detect tumours in patients could greatly improve clinical management.

An interesting aspect of SYSCOL's work regarding the fundamental understanding of the genome of cancer cells is the finding that only a small fraction of a CRC cell's genome is involved in gene expression regulation. This challenges our notion about the genomic complexity of cancer.

The mutual contribution of all partners has resulted in scientific achievements that have clear medical importance and generated 14 peer-reviewed publications in top journals such as Cell, Science and Nature Genetics. Incorporating this information into computational models and tools will lead to the development of novel methodologies for predicting the risk of CRC formation.