Final Report Summary - PANACEA (Quantitative pathway analysis of natural variation in complex disease signaling in C. elegans) Executive Summary:Complex human diseases arise from the interaction between many different genes and the environment and are the main causes of death in Europe. In contrast to the successful identification of genes underlying rare monogenic diseases, studying the genetic basis of common complex diseases has been more challenging. Evidence is mounting to suggest that the genetic background or genotype (i.e. the genetic make-up) has a profound impact on a wide variety of complex disease phenotypes and signaling pathways in humans. But so far, the genetic mechanisms underlying these modifiers are unknown and are difficult to study in humans.Here we investigated the nematode worm Caenorhabditis elegans, which is an important model species, for the identification of genes underlying complex diseases in humans. We took advantage of the natural genetic variation present in different populations and used this to identify key genes which were associated with cancer genetic pathways. By developing specific techniques for knocking down genes in different worm populations we identified novel regulators of cancer pathways. We used this information to mathematically identify, model and predict the development of the worm based on the cancer genetic pathways. This has resulted in a collection of key cancer regulators which have been further investigated for human homologs. A special data base and analysis system has been introduced to facilitate the comparison and investigations into genetic variation underlying complex disease pathways in C. elegans and humans. Project Context and Objectives:Complex human diseases arise from the interaction between many different genes and the environment and are the main causes of death in Europe. Up to 60% of the adult population dies from complex diseases such as cancer and diseases of the circulatory system. In contrast to the successful identification of genes underlying rare monogenic diseases, studying the genetic basis of common complex diseases has been more challenging.Evidence is mounting to suggest that the genetic background or genotype (i.e. the genetic make-up of all alleles at all loci) has a profound impact on a wide variety of complex disease phenotypes. It was shown that the genetic background is likely to influence the onset and progression of tumorigenesis. It was reported that different genotypes were associated with somatic gene expression data in human breast tumors and it was found that the genetic background of different cancer cell lines influenced tumor development. But also in many other complex diseases ranging from urinary stone formation, to autoimmune disorders and retinal degeneration it was found that the genetic background acts as an important modifier of disease pathways. The genetic mechanisms underlying these modifiers are unknown and within PANACEA we address the following two key questions:i) how the genetic background affects complex disease signaling pathways, andii) whether we can predict the effect of the genetic background on these pathways. The European Commission spearheads research programmes which are designed to lead to a better understanding of the genetic variation of complex human diseases. Although many genes have been linked to complex diseases, fundamental research is still needed into why these genes are important, what their role is in the disease and how genetic variation contributes to disease phenotypes. Project Results:Please see final report atttached.Potential Impact:Cancer is one of the most important causes of death and disease in Europe and is strongly related to both environmental and genetic factors. Knowledge of the genetic basis of cancer may lead to new insights into disease pathogenesis, the identification of novel drug targets, and ultimately contribute to human health. Family-based linkage analysis has been very successful in localizing causal variants for monogenic, rare Mendelian diseases. However, success has been rather limited for common diseases, where multiple loci are likely to act in concert and contribute only probabilistically.Testing genetic variants for association between cases and appropriate controls offers a more powerful approach to detect putative causal variants, but require large sample sizes to achieve adequate power. Complete ascertainment of genetic variation by resequencing is the only comprehensive approach to test all variants (both common and rare) directly for association. For the foreseeable future, routine resequencing in thousands of individuals will not be practical. The International HapMap Project provides genome-wide data in 269 individuals from four different population groups, and supports the selection of informative markers (“tag SNPs”). An important outstanding question is whether tag SNPs picked from HapMap will be transferable across independent disease samples for studying the genetic variation of the underlying mechanisms.PANACEA has addressed this question by mobilising expertise and resources on a sufficient scale to give Europe a leading scientific position relating to studying genetic variation of disease signaling pathways. PANACEA provides fundamental knowledge to the European Environmental and Health Strategy (the SCALE initiative). In the long term it will help to combat cancer, which has been a long-standing European priority through the “Europe against Cancer” programme established in 1985 (cf. the proposal for a Council recommendation on cancer screening.PANACEA helps to understand the effect of genetic background on cancer signaling pathways which are highly conserved across species including humans. The project provides increased insight and improvements to current knowledge in relation to complex genetic diseases. Especially, while fitting into the public health framework of European policy, the findings and data base contents of PANACEA contributes to improved understanding in support of future cancer prevention strategies.This project yields insight into the natural variation of disease regulatory networks. The PANACEA developmental model facilitates the identification of multiple drug targets in cancers. The outcomes can be used for prioritizing those targets based on the extent of causal association to disease. Achieving this level of understanding of natural variation in oncogenic pathways opens possibilities to move away from the current “one drug fits all” paradigm and to deliver on the “personalized medicine” promise of getting the right drug to the right person. It is however still a long way toward application of our findings to treatment of human cancers. Our study provides potential novel target genes which can be studied for genetic variation in human populations. Because many genes in the vulva developmental pathway and apoptosis encode for highly conserved human homologs, association studies can be performed on the candidate genes our project have identified. These association studies may run in parallel with regular monitoring studies where DNA samples are taken from patients which are known to have developed carcinomas.List of Websites:http://www.panaceaproject.eu Related documents final1-222936-panacea-final-report-en.pdf
