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Familial Glioma Study Uncovers New Risk Genes

NEW YORK – An international team has tracked down rare glioma-related variants in seven genes through a genome sequencing study that tapped into a collection of familial glioma that began well over a decade ago.

"[T]he Gliogene consortium was formed in 2007 and has enrolled over 15,000 people, creating the largest collection of familial glioma cases in the world," co-senior and co-corresponding authors Matthew Bainbridge, a researcher at Rady Children's Institute for Genomic Medicine, and Melissa Bondy, an epidemiologist and population health researcher at Stanford University School of Medicine, noted in an email.

Although as many as one in 10 glioma cases occurs within glioma-prone families, they explained, familial glioma remains rare overall, appearing in roughly one person per 10,000 individuals. Even so, efforts are underway to better understand genetic susceptibility to glioma, since familial glioma can occur relatively early, in young adults.

With that in mind, the researchers relied on whole-genome sequencing to search for glioma-associated germline variants in an exploratory cohort comprised of 203 glioma patients from 189 familial glioma-affected families. They confirmed their findings in a validation group that included another 122 individuals with glioma from 115 affected families. The germline variants were analyzed alongside whole-genome sequences from more than 1,000 unaffected controls between the ages of 45 and 65 years who identified as non-Hispanic white.

As reported in Science Advances on Friday, the team saw an overrepresentation of 54 variants in 28 genes, which turned up in 50 families in the discovery or validation groups, including seven genes affected by rare deleterious mutations in both cohorts.

The initial analyses unearthed glioma-related copy number changes in HERC2, for example, while analyses on a Genomics England dataset led to rare, deleterious HERC2 germline mutations in two more individuals with glioma.

"[T]his study is the first to link HERC2 to any cancer predisposition," Bainbridge and Bondy noted, adding that the gene is known to contribute to cell cycle regulation, mitochondrial function, and DNA damage response processes.

The analyses also pointed to overlap between glioma susceptibility genes and genes that have been linked to the risk of other cancer types in the past, they pointed out, including BRIP1, an ovarian cancer-associated gene, and POLE, which has been linked to colon cancer.

Finally, the team uncovered suspicious variants in noncoding regions that appear to mediate the activity of still other genes in the germline. In particular, familial glioma risk appeared to coincide with higher-than-usual levels of transcription factor binding site mutations falling upstream of genes such as ZC3H7B, DMBT1, and HP1BP3.

"This is the first study to look at noncoding, functional variants in glioma," Bainbridge and Bondy said.

In follow-up CRISPR gene editing experiments, the researchers saw a significant dip in survival in mouse models of glioma that were missing the ZC3H7B, DMBT1, and HP1BP3 genes, while tumor RNA sequencing experiments pointed to extensive gene expression shifts in the absence of the genes.

Together, the identification of new risk genes for familial glioma "provides the opportunity to explain to affected families why they are at risk, offer peace of mind to those who do not carry the causative mutation, and improve monitoring for those who do," Bainbridge and Bondy said.