Researchers have identified the first gene associated with familial glioma.

An international consortium of researchers led by Baylor College of Medicine has identified for the first time a gene associated with familial glioma (brain tumours that appear in two or more members of the same family) providing new support that certain people may be genetically predisposed to the disease.

It is widely theorised by the medical community that there is no association between family history and development of glioma. Because researchers know very little about the contributing genetic factors, when cases occur in two or more family members, it is viewed as coincidental.  By understanding more about the genetic link, the team hope to improve treatments and preventive strategies for those with a family history of glioma.  The group estimate that approximately five percent of brain tumours run in families.  The study is published in the Journal of the National Cancer Institute.

The team have been researching familial glioma for nearly 30 years, and this study is really the first time the medical community have had a hit when it comes to identifying a gene that is potentially associated with predisposition to the disease.

The study was conducted through the Gliogene Consortium, a collaborative group of familial brain tumour researchers from around the world, which is primarily supported by the National Cancer Institute.  The Gliogene Consortium recruited 435 families in which glioma occurred from 14 centers in the United States, Sweden, Denmark, The United Kingdom and Israel. The recruitment occurred between 2007 and 2011.

The team applied an advanced method of genetic testing called whole exome sequencing (which determines the DNA sequence of the exons, or protein-coding regions, of tens of thousands of genes simultaneously) on 90 individuals with glioma from 55 families enrolled in the Gliogene project.

The researchers then combed through the sequencing data and identified mutations in a gene called POT1, which was present in two of the families.

In one family, six members harboured a mutation of POT1 that is rarely seen in other populations, and among them three developed glioma. In another family, six individuals carried a different mutation in the POT1 gene and two developed glioma.  The team further validated the finding in a separate group of individuals and families with glioma in which they identified an additional mutation in POT1 in one family.

The team state that they are just learning about the risk of cancer associated with POT1 mutations adding that some of the other family members who carry the mutation may develop brain tumours later in life.  The family members who had the POT1 mutation but not glioma, were younger than the ones who developed the disease.

The mutations in the POT1 gene are predicted to result in a disruption in a region of the POT1 protein that is important for its function at telomeres, the protective caps at the end of chromosomes.  The team summise that POT1 modulates the activity of telomerase, a highly regulated enzyme that lengthens telomeres.  This is a very important process, and when the process is disrupted with a mutation in a gene like POT1, the telomeres elongate.

The researchers state thtat although short telomeres have been implicated in a wide range of cancers, longer telomeres have previously been associated with some cancers as well.

POT1 has also recently been observed in familial melanoma in association with longer telomeres by another research team, which was not at all surprising to the team in the current study, as they had previously reported a higher incidence of melanoma in first degree relatives of glioma patients than expected.

In the Gliogene study, the mutations were associated with oligodendroglioma, a lower grade glioma, which is more sensitive to radiation therapy.

The team will do additional research to see how frequent the mutation is in familial gliomas and if it is also associated with higher grades of the disease.  The team say that as they learn more about POT1 and familial glioma, it may help them in counselling families about glioma risk or possibly point the way to new therapeutic targets and that this is the beginning of defining the genes for familial glioma.

The team suspect there could be a number of other genes associated with familial glioma and plan to investigate them in the future.

Source:  Baylor College of Medicine