Localizing genes and mutations involved in low-grade glioma: a registry-based study
01 / 2001 - 12 / 2004
Despite being rare, brain tumors are a major cause of death in children and young adults and inevitably seriously affect quality of life. Specific genetic or environmental risk factors are poorly defined. For low-grade gliomas, which occur only in 1 per 100,000 person-years, the small gender differences and almost constant age distribution suggest a limited role for exogenous (environmental) factors. Family studies indicate that genetic factors, either by themselves or in interaction with environmental factors, most likely contribute to the pathogenesis of the disease. However, the number of families with multiple cases is low, limiting the possibility of the identification of genes involved using classical methods such as linkage and sib-pair analysis. We intend to follow a population-based approach in genetically isolated populations. Disease causing genes are relatively easy to localize in such populations, because a major reduction in genetic variability occurs as a result of genetic drift. - Aim: The aim of the present study is to localize genes involved in low-grade glioma using cases derived from genetically isolated populations. Patients will be ascertained through the Eindhoven Cancer Registry of the Comprehensive Cancer Centre South (IKZ) and the departments of Neurosurgery of the Elisabeth Hospital Tilburg and Radiotherapy at the Verbeeten Institute in the Southern part of the Netherlands. To increase the a priori chances of success, the proposed study will initially focus on low-grade glioma as etiology of the tumors in this groups appears to be less related to environmental factors; the lower mortality rate allows greater chance of finding patients for interview. For this study, a genomic search will be conducted in a series of patients (N=25) that can be linked to a common ancestor through genealogical research and who therefore most likely have inherited a common (susceptibility) gene for low-grade glioma. To localize the gene involved, a powerful statistical method developed for studies in genetically isolated populations in the Netherlands will be used. We aim to identify haplotypes shared by patients with low-grade glioma, which will be a first step towards the identification of gene(s) involved in low-grade glioma. The contribution of the risk haplotype(s) to the prevalence of low-grade glioma will be studied in a series of 100 patients derived from the catchment area of the cancer registry and the Tilburg centre for Neurosurgery and Radiotherapy. We have conducted pilot work to examine the feasibility of this project. Through data provided by the Eindhoven Cancer Registry we have identified all cases of glioma from a single genetic isolated population in the southern Netherlands and have identified several apparent clusters of cases. In one of these clusters, the genealogy of 12 patients has been thoroughly investigated resulting in a common ancestor for 9 patients. This provides strong preliminary evidence that a genetic cause of glioma may exist in this extended family. - Relevance: Identification of genes involved in the pathogenesis of glioma may have important implications for the understanding of glioma, as it will reveal which proteins (i.e., the products of the genes) play a role in the disease etiology and progression. Ultimately, the understanding of the role of genetic factors in the risk of glioma may lead to models for the disease, which can be used for development of therapeutic strategies.