Stanford Scientists Identify Genes Linked to Familial Brain Cancer

A recent scientific study conducted at Stanford University focused on investigating the genetic factors underlying glioblastoma, a rare form of brain cancer. With a research cohort of over 15,000 individuals and around 350 cases of familial glioma identified, the study has made significant strides in discovering specific genes and non-coding regions associated with this condition. These findings open up new possibilities for screening methods and future treatment approaches.

Led by a Stanford Medicine researcher, an international collaboration has identified over 50 genes linked to glioma, a rare type of brain cancer. While the majority of gliomas occur sporadically, a small portion is inherited.

In 2013, Carrie Davis Lebovich and Hadley Rierson, two sisters, faced a frustrating situation. Their father, Jon Davis, aged 69, had recently been diagnosed with glioblastoma, the same type of brain cancer that had taken their grandmother’s life three decades earlier. Given the rarity of glioma, with only approximately 24,000 cases diagnosed annually in the United States, they believed that the chances of the disease affecting their family again were slim.

“When we asked his doctors if this was related to the glioblastoma that killed our grandmother, they all said no,” recalled Rierson. “They told us that brain tumors occur randomly and that our family’s experience was merely a coincidence.”

However, the sisters remained unconvinced.

After conducting thorough research, Lebovich and Rierson connected with Dr. Melissa Bondy, who was then affiliated with Baylor College of Medicine in Houston. Dr. Bondy, currently serving as the Chair of the Department of Epidemiology and Population Health at Stanford School of Medicine, leads an international consortium called Gliogene, which aims to identify the genes associated with familial glioma, a type of brain cancer that includes glioblastoma.

Dr. Bondy reassured the sisters that, contrary to what their father’s doctors had said, a small fraction of glioma cases were indeed familial. Pinpointing the genes involved could not only help determine which family members are at higher risk of developing brain cancer but also shed light on the disease’s biology and guide future treatments. To achieve this, they needed genetic samples from as many patients and their family members as possible.

The sisters immediately volunteered for the study.

Now, Dr. Bondy, who also serves as the Associate Director for Population Health Sciences at the Stanford Cancer Institute, along with her collaborators in Gliogene, has identified several genes associated with familial glioma. Among these genes, two are also linked to ovarian and colon cancers. Additionally, they discovered mutations in three non-coding regions of the genome, which affect the production of proteins.

Their research findings were published on April 28 in Science Advances.

“The discovery of these new genes and non-coding regions holds immense value for families affected by glioma,” stated Dr. Bondy. “These findings provide an opportunity to explain to affected families the reasons for their increased risk, bring peace of mind to those who do not carry the causative mutation, and improve monitoring for those who do.”

The senior authors of the study include Dr. Matthew Bainbridge, the Associate Director of Clinical Genomics Research at Rady Children’s Hospital San Diego, and Dr. Benjamin Deneen, a professor at Baylor College of Medicine. The lead author of the research is Dr. Dong-Joo Choi, a postdoctoral scholar at Baylor.

Familial glioma, the rarest cases within an already rare cancer, encompasses various subtypes of brain cancers such as glioblastomas, astrocytomas, and brain stem gliomas. These cancers originate from glial cells in the brain that support the neurons. Although some are slow-growing and relatively treatable, the prognosis for many gliomas remains poor. According to the National Brain Tumor Society, the average survival time for glioblastoma patients is eight months after diagnosis, with only 6.8% surviving beyond five years.

The majority of gliomas occur sporadically and lack a clear genetic cause. Only about 5% of cases are familial, affecting two or more members of the same family. Dr. Bondy and her colleagues aim to identify the genes associated with these rare familial cases. However, to accomplish this, they need to enroll as many individuals as possible in the Gliogene study. Currently, the study has enrolled over 15,000 people and identified approximately 350 cases of familial glioma.

Jon Davis, the father of Carrie Davis Lebovich and Hadley Davis Rierson, passed away in July 2014, just 13 months after his glioblastoma diagnosis. In December 2014, Dr. Bondy and other Gliogene consortium members announced the discovery of one of the initial genes associated with familial glioma: POT1. Researchers found that mutations in POT1 increased the risk of developing glioma.

To identify additional genes and DNA regions related to brain cancer, Dr. Bondy and her colleagues sequenced the entire genomes of 325 individuals with glioma from 304 families with a history of the disease. They compared these genetic sequences with those of over 1,000 individuals without brain cancer.

The researchers identified six mutations in a gene called HERC2 that were associated with familial glioma. The protein produced by the HERC2 gene plays a role in DNA repair and cell cycle control. Although these functions are shared with many other proteins associated with cancer, HERC2 had not previously been linked to the disease.

Two other genes, BRIP1 and POLE, which were also found to have mutations in familial glioma cases, have been associated with ovarian and colorectal cancers, respectively.

Using CRISPR genetic engineering, the researchers deleted several candidate genes in embryonic mice to induce the development of glioma. They observed that the loss of three genes—DMBT1, HP1BP3, and ZC3H7B—correlated with reduced survival and increased tumor growth in the animals.

In total, the researchers identified 54 mutations in 28 genes or non-coding regions associated with familial glioma within 50 out of the 304 families in the Gliogene study. Many of these genes are involved in cell division, blood vessel development, and immune regulation, all of which contribute to tumor growth.

Dr. Bondy remarked, “This disease is so rare, and the lack of effective treatments for many brain tumors is disheartening. My hope is that one day, I will be able to provide answers to people who ask me, ‘What are my chances of developing a glioma?'”

For Lebovich and Rierson, this study brings hope. Any lingering doubts about their family’s brain cancers being mere coincidences vanished when their aunt succumbed to glioma in 2017. They have devoted their time and energy to raising awareness about familial glioma and encouraging individuals from affected families to participate in the Gliogene study.

“Participating in the study is incredibly easy and painless,” said Rierson, emphasizing that participants only need to provide a saliva sample through the mail.

Lebovich added, “Hadley and I faced many closed doors. We felt very isolated, struggling to obtain information and being told to move on. But when we reached out to Melissa, she spoke with us on the same day. It was an immense relief. She has been an incredible partner.”

“Melissa and the Gliogene collaborators are our family’s only hope for future generations,” Lebovich continued. “But we need people to participate in the study. The more genes we identify as associated with the disease, the better we can screen potential carriers and personalize treatments. But without knowledge of the genes involved, we cannot take any action.”

The study received funding from the National Institutes of Health, the National Institute for Health Research and National Health Service England, the Wellcome Trust, Cancer Research UK, and the UK’s Medical Research Council. 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.

Individuals concerned about familial glioma can find more information at gliogene.org.

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More about familial glioma

• Stanford Medicine
• Gliogene
• Science Advances: “The genomic landscape of familial glioma”
• National Brain Tumor Society
• National Institutes of Health
• National Institute for Health Research
• Wellcome Trust
• Cancer Research UK
• UK Medical Research Council