In 2007, the National Brain Tumor Society provided funding for an international project to search for more clues to one of the biggest mysteries of brain tumors – what causes them to develop. This week, researchers from this project, dubbed the Gliogene Consortium, published preliminary results from their study, which suggest rare mutations in a gene called POT1 could be related to an increased risk for developing the brain tumor, oligodendroglioma.
“It is widely thought amongst the clinical community that there is no association between family history and development of glioma,” said Melissa Bondy, PhD, associate director of cancer prevention and population sciences at Baylor University’s Dan L. Duncan Cancer Center, and the study’s leader. “Because we know very little about the contributing genetic factors, when cases occur in two or more family members, it is viewed as coincidental.”
Now, as Dr. Bondy notes, this is the first time the field has identified a specific gene that may make a small subpopulation of people more likely to develop a glioma, specifically an oligodendroglioma.
“These findings still need to be validated, but this an exciting development in our quest to better understand this disease,” says Carrie Treadwell, Chief Research Officer at the National Brain Tumor Society. “This discovery will help advance our understanding of the causes of oligodendroglioma, and as a result we hope new precision treatments can be developed that target the underlying mechanisms that give rise to these gliomas.”
It must be emphasized that the cause of gliomas is complex and may result from both inherited and non-inherited gene alterations, as well as environmental interaction. In fact, the majority of gliomas are still considered sporadic in origin, with current estimates that only about 5% of all brain tumors are inherited.
In the Gliogene study, which took place across 14 centers around the world, 435 families in which two or more family members had been diagnosed with a glioma (a category of malignant brain tumors including astrocytomas, oligodendrogliomas, and glioblastoma multiforme) were enrolled. Researchers then began looking for common genetic links in families that had multiple members fighting the disease. In the first 55 families analyzed, two different families were found to carry mutations in a gene called POT1. In both of these families, more than one relative developed oligodendroglioma. In one family, six members had a mutation and three developed oligodendroglioma. In the second family, six members also had a mutation (that differed to the one found in the first family), and two developed oligodendroglioma. Further investigation in a separate cohort of 264 individuals from 246 families identified an additional third mutation in POT1 in another family.
These findings may indicate that the “penetrance” of the reported inherited mutations in the gene – that is the proportion of patients who have the mutation who actually develop the disease – is not high (a disease is said to have “complete” penetrance if clinical symptoms are present in all individuals who have the disease-causing mutation). This means not every person carrying a mutated variant of the POT1 gene will necessarily develop an oligodendroglioma. This is because complex disorders, like cancers, are, again, thought to result from the accumulating effect of multiple, rare mutations occurring over time, and often influenced by the environment and other risk factors not yet known.
As Dr. Bondy puts it, “This finding could be an important piece of a very complex puzzle.”
Other emerging evidence supporting the premise that the development of glioma may involve a heritable component, includes results from what are called case-control, genome wide association studies (like those reported here), in addition to familial analyses like those done in the Gliogene Consortium, and several rare inherited syndromes that arise from known single gene mutations (see insert).
Dr. Bondy and her colleagues hope their initial report will just be the beginning of an effort to comb through the entire genomes (which possess tens of thousands of genes at any given time) of more families to find a more complete picture of the genetic risk factors for oligodendrogliomas, and all gliomas. Her team is committed to performing additional research to better understand how frequently POT1 mutations occur, the actual penetrance of the mutations, by what percentage carrying alterations in the gene actually increases a person’s risk of developing oligodendroglioma, and if POT1 mutations are involved in other types of gliomas.
Alterations to the POT1 gene occur in less than 1% of the general population, Dr. Bondy notes. This is a challenge in making quick conclusions from family studies. Sometimes one family, or a small grouping of families, may have a very specific potential mutation associated with the occurrence of a disease that is not applicable to other families with the same cancer. And in the case of this particular study, the authors even note that currently the ability to draw firm conclusions at this point are “limited by the small sample size” analyzed to date. Thus, although the evidence presented in the paper strongly supports a link between POT1 mutations and glioma susceptibility, additional direct experimental evidence will help to fully validate the findings.
Identifying risk factors for brain tumors will aid in moving the field toward a new clinical paradigm, where early detection can become a real possibility and potentially facilitate better management of the disease and more targeted treatments. Indeed, the National Brain Tumor Society’s latest grant as part of our Oligodendroglioma Research Fund will seek to model oligodendroglioma from initiation to better develop therapies that can treat the disease in its earliest, least-aggressive state.
If people would like to learn more about these findings and the possible implications, Dr. Bondy’s team can provide information and advice. Additionally, the Consortium is accepting more families who might be interested in joining the study. Dr. Bondy and her colleagues can be contacted through www.gliogene.org.