GENEPI 2 aims to further develop qualitatively and quantitativly the European tissue bank and database GENEPI-ENTB, established with EURATOM support in FP5. It is dedicated to research in radiation effects and in the genetic determinants of the variation in individual radiosensitivity. With tissues from more than 4.200 patients linked to solid outcome data stored, GENEPI is currently the largest infrastructure in this field worldwide. The final aim is to more than triple that number to enable the selection of statistically relevant groups for analysis and to keep all future avenues of research open. An inestimable plus value for the GENEPI tissues (DNA or lymphocytes and other normal and tumour tissues) obtained from radiotherapy patients, is the data-base linked to it. For each tissue, treatment data (dose distributions with dose gradients, total dose, dose per fraction) and outcome data are recorded. It will be a major objective for GENEPI 2 to develop the tools to make these rich data easily searchable and available for distant querying. Another powerful new feature to be developed in GENEPI 2 aims at creating a logistical shortcut for the quest to identify the hypersensitive phenotype. Tissues will be collected from a group of patients who demonstrated an unexpectedly severe response to RT (+/- 1 out of 1000). This action will necessitate the collaboration of a large segment of the European RT community. Major attention will be paid to all aspects of quality assurance. The Consortium will oversee all protocols, use and access. Finally, a close collaboration will be established with the "GENEPI-Low RT" consortium intent on using the GENEPI resource for its proposed "Low dose radiosensitivity" project submitted for this call as well as with other candidate users a.o. a working party preparing a joint study on radiation response to high doses. ESTRO will be the custodian of ethical issues and handle dissemination, training and project management.
Overall Aim
Tissue banks have become an essential infrastructure for biomedical research, molecular biology, genomics and proteomics. For research proposals addressing EURATOM's overall thematic priorities only tissues collected under observance of strictly regulated protocols and linked to data bases, providing very specific and well defined data, most importantly outcome data are of interest. This rationale was at the basis of the establishment of the GENEPI biobank. Just 2 years after the launch of the project, GENEPI was already referred to as "the most comprehensive (tissue bank) in this regard" in a publication of the International Atomic Energy Agency reporting on "radiogenomics and the characterisation of molecular profiles that predict normal tissue and tumour radioresponse" (Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1264-73)
Although GENEPI 1, with already tissues from more than 4.200 patients documented in its database, has well exceeded the goals stated in its work plan, we are still far from having reached the final goal of a GENEPI biobank with at least 15.000 tissues and corresponding data sets. This is the minimum number of samples that according to a bio-mathematical model, computed for GENEPI 1, was estimated to be necessary for the selection of statistically relevant cohorts for analysis in present and future research. For the selection of homogeneous groups indeed a multitude of parameters have to be taken into account such as tumour and therapy related (e.g. treatment, radiation dose and fractionation schedule, as well as patient confounding factors (e.g. age, gender, co-morbidities) . For this reason the main objective of the project is the quantitative and qualitative further development of the infrastructure to be able to match all present and future requirements of the research community.
Quantitative development
During GENEPI 1 a broad network of partner institutes contributing to the GENEPI resource was built up. This collaboration will continue in GENEPI 2. In addition, the project leader, leading the EORTC radiotherapy group, and the project partners will systematically screen the protocols of new collaborative clinical trials on their suitability for enrolment in the GENEPI project. Although some further accrual of retrospective tissues is foreseen, the emphasis in GENEPI 2 will be on prospective tissue collection. In addition to lymphocytes, plasma, skin, mucosa and tumour cells, the culture of fibroblast cell lines and the submission of dosimetry and clinical data will be encouraged.
Qualitative development
A unique advantage of the GENEPI infrastructure for the purposes of research of interest to the EURATOM objectives is that the investigators will be able to select tissues with well defined characteristics.
2.1 The GENEPI database contains per submitted patient, a minimum data set that is in the public domain. This allows scientists to screen the suitability of the infrastructure for their research purposes, prior to submitting an official application for access. For a more advanced search however, in which dosimetric data are considered, the scientist still has to be referred to the contributing centre where these data (dose, time, fractionation characteristics, dose-volume histograms, dose distributions in the tumour and surrounding tissues) are stored in hard copy form. To enhance the accessibility, the search ability, briefly, the general performance of the data base, new tools will have to be developed to register these complex data, generated by a variety of software systems, in a uniform format in the central database. In order to provide for all partners and investigators involved access to a common software platform for distant data entry and querying, an information grid structure will have to be developed.
2.2 So far 2 applications for the use of the GENEPI infrastructure were received. Any partnership agreement with research consortia will include a commitment to feed genetic data (SNPs, Microarrays etc) derived from GENEPI tissues, back into the GENEPI database. Also for this purpose new database functionalities will have to be developed.
2.3 A repository for tissues obtained from individuals showing severe adverse reactions to normally well tolerated dose levels, will be created. Every radiation oncologist has etched in his mind the memory of patients with unexpectedly severe reactions to radiation. Such events occur on average only in 1 out of 1000 patients. The availability of a number of tissues obtained from such severe "overreactors" might be an invaluable asset and shortcut for research. For this purpose an appeal will be launched both to university departments and general hospitals to collaborate for this. Ethical and especially quality assurance (QA) issues involved in this task will be given due consideration.
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