Genes linked to familial brain cancer identified in Stanford Medicine-led study

An international effort led by a Stanford Medicine researcher finds more than 50 genes linked to glioma — a rare brain cancer. Although most gliomas are sporadic, a minority are inherited.

- By Krista Conger

Carrie Davis Lebovich (left) and Hadley Davis Rierson were convinced that brain cancer ran in the family when their father, Jon Davis, was diagnosed with the same rare type his mother died from. Researchers at Stanford Medicine proved them right.
Connie Miller

Sisters Carrie Davis Lebovich and Hadley Rierson were frustrated. It was 2013 and their 69-year-old father, Jon Davis, had just been diagnosed with glioblastoma — the same rare type of brain cancer that had claimed his mother’s life 30 years earlier. Only about 24,000 people in the United States are diagnosed each year with glioma, and they believed the odds of lightning striking twice in the same family were slim.

“Our first question to his doctors was, ‘Is this related to the glioblastoma that killed our grandmother?’,” Rierson recalled. “And they all said no.” Brain tumors happen randomly, the sisters were told. Their family’s experience was just a coincidence.

The sisters didn’t believe them.

After some dogged research, Lebovich and Rierson found Melissa Bondy, PhD, who was then at Baylor College of Medicine in Houston. Bondy, now the chair of the department of epidemiology and population health at the Stanford School of Medicine, directs an international consortium called Gliogene aimed at identifying genes involved in familial glioma — a class of brain cancer that includes glioblastoma.

Bondy assured the sisters that, yes, despite what their father’s doctors had told them, a small minority of glioma cases are familial. Pinpointing the genes involved could not only help identify which members of affected families have an increased risk of brain cancer but also shed light on the biology of the disease and drive future treatments. To do so, they needed genetic samples from as many patients and their family members as possible.

The sisters immediately signed on.

Now, Bondy, who is the associate director for population health sciences at the Stanford Cancer Institute, and her Gliogene collaborators have identified several genes associated with familial glioma — two of which are also associated with ovarian and colon cancers. They also found mutations in three locations of the genome called non-coding regions that affect which genes are made into proteins.

They described their findings in an article published April 28 in Science Advances.

“The identification of these new genes and non-coding regions is of immense value to families affected by glioma,” Bondy said. “The discovery 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.”

Other senior authors of the study are Matthew Bainbridge, PhD, associate director of clinical genomics research at Rady Children’s Hospital San Diego, and Benjamin Deneen, PhD, professor at the Baylor College of Medicine. Dong-Joo Choi, PhD, a postdoctoral scholar at Baylor, is the lead author of the research.

Rarest cases within a rare cancer

Gliomas encompass several subtypes of brain cancers including glioblastomas, astrocytomas and brain stem gliomas. They arise from cells in the brain called glial cells that support the brain’s neurons. Although some are slow growing and relatively treatable, the prognosis for many of these cancers is poor. According to the National Brain Tumor Society, the average survival of glioblastoma patients is eight months after diagnosis; only 6.8% are alive after five years. 

Most gliomas are sporadic and seem to have no clear genetic cause. Only about 5% of gliomas are familial, afflicting two or more members of the same family. Bondy and her colleagues want to identify the genes involved in these, the rarest cases of an already rare cancer. But to do so they need to enroll as many people as possible in the Gliogene study. So far, the study has enrolled over 15,000 people and identified about 350 cases of familial glioma.

Jon Davis and his sister, Beth Karren, both died from brain cancer.
Courtesy of the Davis family

Jon Davis died in July 2014, just 13 months after his glioblastoma diagnosis. In December 2014, Bondy and other members of the Gliogene consortium announced the discovery of one of the first genes associated with familial glioma — POT1. Mutations in POT1 carry an increased risk of developing glioma, the researchers found.

To find additional genes and DNA regions associated with brain cancer, Bondy and her colleagues sequenced the entire genomes of 325 people with glioma from 304 families with a history of the disease. They compared their genetic sequences with those of more than 1,000 controls without brain cancer.

They found six mutations in one gene, called HERC2, that were associated with familial glioma. The protein made from the HERC2 gene is involved in the repair of damaged DNA and the control of the cell cycle. Although these roles are shared with many other cancer-associated proteins, the HERC2 protein was not previously associated with cancer.

Two other genes — BRIP1 and POLE — that were also mutated in familial glioma cases have been associated with ovarian and colorectal cancers, respectively.

The researchers used CRISPR genetic engineering to delete several candidate genes in embryonic mice treated to develop glioma and saw that the loss of three of them — DMBT1, HP1BP3 and ZC3H7B — correlated with a decrease in survival and an increase in tumor growth in the animals. 

All told, the researchers identified 54 mutations in 28 genes or non-coding regions that were associated with familial glioma in 50 out of 304 families in the Gliogene study. Many of the genes are involved in cell division, blood vessel development and immune regulation — all factors that can contribute to tumor growth.

“This is such a rare disease,” Bondy said. “The worst part is there is currently no effective treatment for many brain tumors. My hope is that one day I can answer people who ask me ‘What is my chance of developing a glioma?’”

‘Such a huge relief’

For Lebovich and Rierson, the study brings hope. Any lingering chance that their family’s brain cancers were simply coincidental vanished when their father’s sister died from a glioma in 2017. They’ve devoted their time and energy to spreading the word about familial glioma and encouraging people in affected families to join the Gliogene study.

“It couldn’t be easier or less painful to participate,” said Rierson, noting that participants simply submit a sample of saliva through the mail.

“Hadley and I had so many doors shut on us,” Lebovich said. “It felt very lonely. It was hard to get information; we were told move on. But when we reached out to Melissa, she was on the phone with us that same day. It was such a huge relief. She has been an unbelievable partner.”

“Melissa and the Gliogene collaborators are our only hope for the future generations of our family,” Lebovich continued. “But we need people to participate in the study. The more genes we know are associated, the better you can screen potential carriers and possibly tailor treatments. But you can’t do anything if you don’t know the genes.”

People who feel their families may be affected by familial glioma can learn more at gliogene.org.  

Researchers from the University of Texas Health Science Center School of Public Health, Duke University and Umea University in Sweden also contributed to the study.

The study was funded by the National Institutes of Health (R01CA217105, X01HG009883, R01CA119215, R01CA139020, U54HG003273 and UM1HG008898), the National Institute for Health Research and National Health Service England, the Wellcome Trust, Cancer Research UK, and the UK’s Medical Research Council.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

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