Final Report Summary - EPISUSCEPTIBILITY (Epigenome and Cancer Susceptibility)
Cancer is a major cause of morbidity and mortality in the aging European population. Although individual variation in the genetic makeup explains a significant proportion of the observed differences in disease susceptibility between individuals and groups, alternative mechanisms are becoming more and more evident. On top of the genetic code lies another one, epigenetic, which consists of DNA methylation and covalent histone modifications, without any alterations in the DNA sequence itself. Epigenetic mechanisms confer different activity to the same genes depending, for example, on the tissue in question, developmental stage, and environmental influences, such as lifestyle and diet, and are important mediators of effects accumulating with age.
This project is designed to identify novel mechanisms of cancer susceptibility by focusing on epigenetic differences between normal and cancer cells. Colorectal carcinoma provides an excellent model to examine epigenetic changes in cancer development because it arises stepwise during several years and the process can be accelerated or halted by common factors like inherited susceptibility and diet. We use well-established human syndromes with increased risk of colorectal and other cancers (designated as HNPCC and FAP) as well as their murine counterparts as tools. Some epigenetic alterations are present from birth already and occur in most tissues of an individual (constitutional epimutations). Other changes are restricted to a certain tissue only (e.g. colorectal mucosa in individuals who later develop colorectal cancer) and become more and more prominent along with transformation from normal to cancer cell and with cancer progression.
Structural changes (mutations) and regulatory changes (epimutations) increase genomic instability, a recognized hallmark of cancer. Genomic instability may take different forms that are well represented in tumors developing in HNPCC and FAP. DNA mismatch repair (MMR) corrects errors during DNA replication and plays a crucial role in cancer avoidance. Over 3,000 different sequence variants in MMR genes are known to occur worldwide, but sequence information alone is often insufficient to distinguish harmful variants from innocent ones. We have developed functional strategies which make this distinction possible. Moreover, inherited sequence changes explain only a minority of familial clustering of colorectal cancer. Our results show that some 10% of mutation-negative colorectal cancer families with evidence of MMR gene malfunction are due to constitutional epimutations of MMR genes. Molecular profiling of normal, preneoplastic, and cancer tissues from hereditary and sporadic cases has identified epigenetic biomarkers able to distinguish the tissue of origin, MMR status, and sporadic vs. hereditary disease, as well as the propensity for progression. These markers may aid in sub-classification of colorectal and endometrial cancers for preventive or therapeutic purposes. Finally, dietary intervention studies conducted in mice provide strong evidence that the so called Western diet, which is rich in red meat, saturated fat and sugar and poor in dietary fiber, vitamins, and minerals, is associated with changes in the expression of cancer-relevant genes in the bowel mucosa. These changes in part depend on inherited susceptibility and may involve the epigenetic system to develop.
Combined information of constitutional and acquired changes, epigenetic and genetic, can be clinically utilized to develop more accurate predictors of cancer risk. Unlike genetic changes, epigenetic changes are potentially reversible, making them attractive targets for preventive and therapeutic interventions.
This project is designed to identify novel mechanisms of cancer susceptibility by focusing on epigenetic differences between normal and cancer cells. Colorectal carcinoma provides an excellent model to examine epigenetic changes in cancer development because it arises stepwise during several years and the process can be accelerated or halted by common factors like inherited susceptibility and diet. We use well-established human syndromes with increased risk of colorectal and other cancers (designated as HNPCC and FAP) as well as their murine counterparts as tools. Some epigenetic alterations are present from birth already and occur in most tissues of an individual (constitutional epimutations). Other changes are restricted to a certain tissue only (e.g. colorectal mucosa in individuals who later develop colorectal cancer) and become more and more prominent along with transformation from normal to cancer cell and with cancer progression.
Structural changes (mutations) and regulatory changes (epimutations) increase genomic instability, a recognized hallmark of cancer. Genomic instability may take different forms that are well represented in tumors developing in HNPCC and FAP. DNA mismatch repair (MMR) corrects errors during DNA replication and plays a crucial role in cancer avoidance. Over 3,000 different sequence variants in MMR genes are known to occur worldwide, but sequence information alone is often insufficient to distinguish harmful variants from innocent ones. We have developed functional strategies which make this distinction possible. Moreover, inherited sequence changes explain only a minority of familial clustering of colorectal cancer. Our results show that some 10% of mutation-negative colorectal cancer families with evidence of MMR gene malfunction are due to constitutional epimutations of MMR genes. Molecular profiling of normal, preneoplastic, and cancer tissues from hereditary and sporadic cases has identified epigenetic biomarkers able to distinguish the tissue of origin, MMR status, and sporadic vs. hereditary disease, as well as the propensity for progression. These markers may aid in sub-classification of colorectal and endometrial cancers for preventive or therapeutic purposes. Finally, dietary intervention studies conducted in mice provide strong evidence that the so called Western diet, which is rich in red meat, saturated fat and sugar and poor in dietary fiber, vitamins, and minerals, is associated with changes in the expression of cancer-relevant genes in the bowel mucosa. These changes in part depend on inherited susceptibility and may involve the epigenetic system to develop.
Combined information of constitutional and acquired changes, epigenetic and genetic, can be clinically utilized to develop more accurate predictors of cancer risk. Unlike genetic changes, epigenetic changes are potentially reversible, making them attractive targets for preventive and therapeutic interventions.