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About 2 to 4% of all cancers have an established genetic origin, due to the association of hereditary gene mutations with higher cancer risk. Though the etiology of the remaining cancers is elusive, it is estimated that about 80% have an identifiable cause related to lifestyle or environment. Compelling evidence for the implication of specific environmental factors and lifestyles (non-hereditary “cause”) in tumor development, however, is available for only a small subset of cancers. This represents a major curb on the strategies of cancer prevention.
Recent findings suggest that environmental factors and lifestyles implicated in tumor development might increase cancer risk by inducing alterations of chromatin (epigenomic modifications or epimutations) without causing changes in the underlying DNA sequence. On the other hand, a large body of evidence is emerging to suggest that epigenomic changes are causally linked to oncogenesis and tumor progression. Thus, epigenomic changes might represent ideal molecular markers of the carcinogenic effects of specific environmental factors and lifestyles.
One critical issue in analyzing the early epigenomic effects of cancer-associated environmental factors and lifestyles is the choice of the cell target. Since the target cell must survive long enough in the human tissues to allow accumulation of genomic damage, tissue stem cells are obvious candidates notably, comparison between the epigenetic characteristics of cancer cells and stem cells suggest that epigenetic deregulation may program stem cells for cancer-like behavior long before they are visually identifiable as tumor cells.
We will test the hypothesis that environmental factors and lifestyles increase the risk of cancer development by inducing specific epigenomic changes tissue stem cells. We expect that this epigenomic changes might then be used as molecular markers for the quantitation of the environmental risk of cancer. We will pursue this goal by setting-up a number of suitable cancer models for the study of the carcinogenic effects of lyfestyle and environment (obesity, inflammation, UV, aging). |
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Investigation of genetic networks underlying disease phenotypes requires holistic approaches for the analysis of DNA (genome), chromatin (epigenome), RNA (transcriptome) and proteins (proteome).
Transcriptome analysis are successfully performed using one of the many available microarray platforms, which are currently available at the Campus.
The technological approaches for the global analyses of the genome and the epigenome (Genome and Epigenome Analyses) have been revolutioned by the introduction, in 2004, of the so-called “next-generation sequencing” approaches. These technologies produce millions of DNA sequence reads in a single run and are bringing genetics into a new era, whereby complex phenotypes can be reduced into defined genotypes and “epi-genotypes”. The final attainment of this goal needs re-sequencing of thousands of genomes, a task that is prevented by the yet too high cost of the next-generation sequencing technology (about half million Euros per one genome). A next-generation sequencing platform is available at the Campus.
Proteome analysis Mass spectrometry (MS)-based proteomics is indispensable for the quantitative study of protein-protein interactions on a small and proteome-wide scale, protein mapping of organelles, characterization of post-translational modifications, acquisition of protein catalogues for different cellular states, tissues or organisms. The needed technologies are available at the Campus.
All the Genomic Screening facilities already present in the Campus will be accessible for the needs of the scientific programs of the “ISI-GenOmics - Center of Genomic Science of IIT@SEMM”. The Genomic Technologies Unit of the “ISI-GenOmics - Center of Genomic Science of IIT@SEMM” will be mainly centered on the improvement and set-up of next-generation and next-next-generation sequencing technologies, particularly for the needs of the “Environmental Cancer Risk Assessment project”.
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EHS