As the saying goes, knowledge is power. But, sometimes, it can also be scary.
“Oh, it’s horrible!” says Carrie Davis about her quest, which she shares with her sister Hadley, to help better understand links between inheritable genes and brain tumors. She continues, “Every time I get a headache I think I have a brain tumor. And I worry about my kids. And Hadley worries about her kids. I mean, this happened three times in our family. We have our father’s genes. It’s terrifying. But what option do you have but to try and help get to the root of the problem? That’s the only option.”
The roots of Carrie and Hadley’s saga run back to the early 1980s when their paternal grandmother was diagnosed with glioblastoma. She would ultimately pass due to her illness. For the next three decades, they assumed her tumor was a random, sporadic occurrence. That changed in mid-2013 when their father received the same diagnosis. Sadly, he passed away the following July.
”We thought it was really crazy to have two of these rare tumors in our family,” says Hadley. “But most of the doctors we spoke with at the prestigious hospital where our father was treated told us that it was just that — coincidental.”
While glioblastoma is the most common brain cancer, the roughly 13,000 new diagnoses annually make the tumor a relative (and technically) rare disease. The chance that any individual will be diagnosed with a glioblastoma in their lifetime is far less than one percent. The odds that two blood relatives will both receive the diagnosis are even more infinitesimal.
Then, in the spring of 2017, the Davis’s aunt — their grandmother’s daughter and their father’s older sister — was diagnosed with a grade III astrocytoma, a high-grade glioma like glioblastoma. Indeed, her tumor eventually progressed into a glioblastoma and ultimately — like her brother before her, and mother before him — she died from the disease.
For us, it confirmed that, ‘Now, OK, there is really no way that anyone could kid themselves that these diagnoses could be coincidences in our family.’Attribution: Hadley
The truth is, even before their father and aunt’s passing the Davis’s fervency for understanding and penchant for action had already started them on a path for answers.
“We’re those kinds of people – if there’s a problem we’re going to try and solve it,” says Carrie. “So we did some sleuthing. And someone mentioned Melissa Bondy’s name. So I wrote her an email. I remember where I was when she wrote back, because I was so surprised. She wrote back almost immediately and said, ‘Let’s get on the phone.’”
That was the summer of 2013. After continuing to bend the ear of any medical professional that would listen during her dad’s many appointments, Hadley had finally secured a name that would set them on their current mission, jotted it down, shared it with Carrie, and precipitated the aforementioned email to Dr. Melissa Bondy.
So we got on the phone with her [Dr. Bondy] and the first thing she said to us was, ‘It can run in families.’ Which in a weird way was a relief, because at least then you can try to find some answers.Attribution: Carrie Davis
Dr. Bondy, Professor of Medicine & Epidemiology, Section Head of Epidemiology and Population Sciences at Baylor College of Medicine and Associate Director of Cancer Prevention and Population Sciences at Baylor’s Dan L. Duncan Comprehensive Cancer Center, has devoted her 30-year career to researching brain tumor susceptibility in families, particularly familial glioma.
Gliomas are a group of brain tumors that include astrocytomas (including glioblastomas), oligodendrogliomas, ependymomas, mixed gliomas, optic nerve gliomas, and brain stem gliomas (including DIPG). These tumors account for 26% of all primary brain tumors, but 81% of all primary malignant brain tumors. Gliomas can affect all ages, but they are most often seen in adults, and can range from low-grade (WHO Grades I and II) to high-grade (WHO Grades III and IV). Little is known about how or why they occur.
Dr. Bondy has her own personal connection to the disease, having lost her grandmother to a glioma. And she, like Carrie and Hadley, has caught herself wondering if she could be at increased risk herself.
“When it is on your mind all of the time it is scary,” Dr. Bondy says. “And we want to be able to give people information, because I know how scary it can be. So we want this research to be done faster.”
In 2007, with financial support from the National Brain Tumor Society, Dr. Bondy launched a first-of-its-kind study attempting to gather clues to one of the biggest mysteries shrouding brain tumors: why they develop. Called Gliogene, Dr. Bondy’s study set out to look for the proverbial needles in a haystack: the little-known population of families for which glioma brain tumors has struck two or more times.
“What we are looking for are rare mutations in families,” says Dr. Bondy. “It’s important to keep in mind that all cancers have a genetic predisposition. And it’s been estimated, for every cancer, that it’s between five- and eight-percent, or maybe as high as 10-percent. But because brain tumors are rare it’s much harder to for us to find these cases that are aggregating, but also because the survival is so low that we don’t get as many people that are living with the disease…by the time people [in families] realize, ‘Ok, now we have a second [diagnosis], and now a third one,’ a lot of the people are already deceased.”
Scouring the DNA* of 101 individuals from 70 families from whom multiple members had been diagnosed with a glioma, Dr. Bondy and her colleagues in the Gliogene consortium identified rare mutations to a gene called POT1 that could be related to an increased risk for developing glioma. Their discovery, published in 2014, was the first time the field has identified a specific genetic variant that may make a small subpopulation of people more likely to develop these types of tumors. However, the sample size of the study was relatively small and the work represented just the opening salvo in the effort to comb through the DNA of families to find a more complete picture of the genetic risk factors for gliomas**.
We are thinking about glioma in the same way that we now approach the BRCA breast cancer genes. We know that BRCA mutations can be inherited and put individuals at a higher risk for breast cancer, so we hope we can identify and generate the same kind of awareness for glioma through enrolling and sequencing families from across the country.Attribution: Dr. Bondy
Following Gliogene’s early success with the POT1 finding, Dr. Bondy and her team received a new grant from the National Cancer Institute that will support the recruitment more families (and for functionalizing the genes they find using CRISPR gene-editing technology in Dr. Ben Deneen’s laboratory at Baylor) and expand Gliogene’s scope.
“We started the first big study, and then I was eager because we started to find promising results, and I wanted to continue this, but still our sample size wasn’t large enough,” she says. “So that’s how this new study got started.”
The next phase of the research will require even more patients and families in order for the study to learn about potential familial links. Gliogene is seeking to recruit at least 200 families to take part in the Gliogene study over the next three years. Participants may be eligible if they and a biological family member both have been diagnosed with glioma (even if the other family member is deceased), or if two biological family members (other than themselves) have been diagnosed. The study is open to patients and families anywhere in the U.S., and can be completed completely over the phone, mail, and internet/email. A blood sample is required for the individual affected with a glioma.
“Dr. Bondy’s team has made it really easy to participate in this study,” says Hadley. “You can do it online and they’ll send you a kit in the mail. It’s not a big commitment in time or energy and this is an opportunity to help your own family, your own relatives, somewhere down the road. This knowledge — discerning the genes that might lead to brain tumors — is an important step in understanding this terrible disease. And we have to learn more about it in order to know how to potentially prevent it.”
Indeed, Carrie and Hadley have first-hand experience with participation. After they reached out to Dr. Bondy in 2013 during the initial phase of Gliogene, the Davis’s got her team everything they could to help them study their family. Through the mail kits provided by Gliogene, the Davis’s provided Dr. Bondy with blood samples from both their father and aunt, as well as another uncle who has not been diagnosed with any glioma.
Participating in Dr. Bondy’s research alone was not enough for Carrie and Hadley, however. They wanted to do more and adopted an “everything we can” approach to help enable Dr. Bondy and get the answers they seek — if not for them, then for their children and grandchildren.
We know realistically this research isn’t going to help us if, God forbid, we found ourselves with this disease one day. But we feel an obligation because this has happened in our family, to move the research forward…So this is our way to pay it forward…We feel an obligation to move the needle.Attribution: Hadley
The two east coast transplants, who now reside in the Los Angeles area, both work in the entertainment industry. And they felt their professional connections and experience could help get the word out about Gliogene and generate awareness to ensure Dr. Bondy reaches her enrollment goal for this next phase of the study.
“We set out to pour whatever resources we could into awareness,” says Carrie. “Our efforts are stymied by the fact that there is no broad awareness about this. So that’s really where we’re focused on in our efforts.”
Yet, their quest was never meant to end at just knowledge and understanding.
“We’re hoping that, eventually, the knowledge will meet the technology, the science, the precision medicine, and all the promising things that cancer research has in store,” Hadley says.
Dr. Bondy is clear about the potential promise and goal of her work. “Our hope is that results from Gliogene will further brain cancer screening and prevention strategies for future generations,” she says.
“What I really want to be able to do in the end is be able to tell people what their risk of developing the disease is based on what genes they might have that could cause the glioma,” Dr. Bondy states.
To get to a BRCA-level of understanding, confidence, and awareness for familial glioma, researchers need more families, larger data sets, and larger sample size to see what genes are important to glioma risk.
“It’s so important to have people like Carrie and Hadley who are willing to participate in the research,” says Dr. Bondy. “Research is knowledge. It gives us information. That’s why it’s important.”
Aptly, the latest phase of the Gliogene study officially launched and opened for enrollment on Wednesday, May 15, 2019.
“There is not a lot we can tell families that have had the awful experience of having not one, but multiple, brain cancers in the family,” says NBTS CEO David Arons. “And for some, it’s a helpless feeling having no idea why — why this happened to them, why it happened to their family. We believe this effort, led by one of the best in the field, is a very constructive avenue for those agonizing over the ‘why’ to participate in research that can possibly get some answers. Additionally, we share Dr. Bondy and the Davis’s hope that this study can lead us one step further toward identifying risk factors which could eventually facilitate potential screening and earlier-detection strategies; something this field has always lacked.”
Interested individuals/families can get more information about participating. The researchers would also like to hear from families that participated in the original, first phase of Gliogene if there are any new updates to their family history.
For those in the brain tumor community without a family history of more than one glioma, who would still like to help (Dr. Bondy says that, “One of our thoughts was that if we identified genes in families that they would be important for us, too, for sporadic cases as well.”), spreading the word about this research is another avenue support the Gliogene effort.
*More specifically the exomes — or the regions of the genome that contains the genes that contain the instructions to make protein products – of these individuals.
**The “penetrance” of the inherited mutations in the POT1 gene – that is the proportion of patients who have the mutation and actually go on to develop the disease – is also not believed to be 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 (which is believed to be less than 1% of the general population) will necessarily develop a glioma. This is because complex disorders, like brain tumors and cancers, are thought to result from the accumulating effect of multiple, rare gene mutations (both inherited and non-inherited) occurring over time and often influenced by the environment and other risk factors not yet known. As Dr. Bondy puts it, these findings “could be an important piece of a very complex puzzle.”