Expanding access to genetic research and care

A genetic counselor using a molecular model to explain aspects of genetic risk.

A genetic counselor using a molecular model to explain aspects of genetic risk.

The impact of nature or nurture on the development of children remains a classic conundrum among all parents. How much of each child’s angelic (or tantrum-filled) temperament extends from DNA or parenting skills has not yet been perfectly explained. While parents often love to take credit for their child’s skills or characteristics, with common exclamations of “she gets that from you” or “he has your ears,” genetics — “nature” — can also bestow negative traits. 

It can feel like a betrayal when a child’s very genes are working against them, predisposing them to or causing certain diseases. Parents — who want nothing but the best for their children — may be at a loss as to what to do when confronted with their child’s inherited risk for a disease. But there is reason for hope: DNA does not determine all fates, and genetic information can be used to help individuals prevent disease and inform the best treatment after diagnosis. 

For example, programs such as exercise and healthy eating can help guide patients through reducing their risk of disease. Genetics can also predict how patients respond to some therapies, enabling more effective and less toxic treatments. However, these benefits of having access to genetic information are not equally accessible to all populations. For many people, genetic analyses are never offered, or they are simply not included in genetic research, this means that research results do not apply to them because people with a similar genetic background have not been included. 

Researchers from St. Jude and across the world are working to address these gaps, learning more about the role of genetics on disease and treatment in populations of different ancestries, such as those of Asian, African, and Hispanic ancestry, who are routinely left out of genetics research. 

Genetics is one origin of different outcomes in childhood cancer

From the Human Genome Project’s completion to today, research has revealed how variations in the 3 billion base pair human genome sequence predispose people to diseases and other health conditions. St. Jude has been a leader in pediatric cancer genetic risk research since the beginning, focusing on the impact of DNA variants in the most common childhood cancer, acute lymphoblastic leukemia (ALL).

One of the reasons scientists have looked to genetics was, and is, the differences in pediatric cancer outcomes. 

“There has been a persistent racial gap in pediatric ALL survival rates,” said Jun J. Yang, PhD, St. Jude Department of Pharmacy and Pharmaceutical Sciences vice-chair, an expert in genetics and ALL. “We see different cure rates of ALL between those of mainly European ancestry, African ancestry and those with Hispanic ethnicity.” Those of non-European ancestry tend to experience lower survival rates than those of European descent.

The difference in outcomes is due to many factors, including environmental, socioeconomic and genetics, all interacting in complex ways. Yang has spent a decade at St. Jude teasing apart the genetic factors that predispose children to cancer and different treatment outcomes to improve their care.

“As a geneticist, my job is to pinpoint exactly what those genetic factors are,” Yang explained. “If I could find a specific gene variant causing the differences, it would open the door for therapy to target that specific pathway or use genetics to guide individualized therapy to reduce excessive toxicity experienced by patients of a particular ancestry.”

One of Yang’s early discoveries at St. Jude was that variations in four genes predispose children to developing ALL. The study in the Journal of the National Cancer Institute showed up to a nine-fold increase in risk in children with multiples of the high-risk genes. Those of Hispanic ethnicity (individuals with greater than 10% Native American ancestry that was also greater than African ancestry in particular) had an increased prevalence of two of the leukemia risk variants compared to those of European or African ancestry. That difference was also reflected in the higher rates of ALL in Hispanic children compared to those with European or African ancestry.

“That research taught me two things,” Yang said. “There are two different sources of these discrepancies. One is the biological difference that we’re seeing between populations of various ancestry drives differences in how people develop cancer and also how they fare with cancer therapy. The second is a data gap; we just don’t study minority populations enough. There’s a paucity of data in minority children with cancer.” 

Treatment outcome differences emerge from a lack of inclusive genetics research

The lack of data about children with cancer from ethnic minority populations in the U.S. has far-reaching consequences. If obtaining data about these groups is never made a priority, then that information is never collected and it will never enter the research paradigm. This leads to far too little information regarding disease risk and progression in these groups.

The problem arises when a treatment is used in people with an under researched genetic ancestry, such as children with Asian heritage. Biology may dictate that children metabolize or react to drugs differently than their peers. For example, Yang spent years studying why thiopurines, a class of chemotherapeutic that is included in a common curative therapy for ALL, displayed toxicity in some patients while being well tolerated by others. 

“We discovered a specific genetic variant in a gene called NUDT15 that’s linked to toxicity of thiopurine,” Yang explained. “When physicians started treating kids of Asian ancestry with this drug in the 70s, they simply extrapolated the dose derived from children of European ancestry, but it didn’t work because Asian children were way too sensitive to thiopurines and couldn’t tolerate it. Now we know why.” Yang published his group’s findings in Nature Genetics.

The St. Jude researchers found the problem arose in the past: The clinical trials that led to the authorization of thiopurine to treat ALL had included mostly children of European descent. The sensitivity variant is rare in that population while common in children of both Asian and Hispanic ancestry. This explained why patients with those heritages experienced a disproportionate amount of toxicity.

To understand the underlying biological mechanism driving these differences, Yang’s lab and his collaborators found the function of NUDT15. Normally, the protein reduces the supply of the active drug metabolite responsible for inducing cell death. The high-risk variant reduces NUDT15 function by anywhere from 75-to-100%, leading to a buildup of the toxic metabolite, even at the standard dosage.

“Physicians empirically figured out that children of Asian descent could only tolerate about half the standard dose,” Yang said. “We showed why that was and shifted the paradigm in terms of how the drug is used for pediatric ALL cases. Now, the FDA has changed their drug label, partly based on our data.”

Researchers continue efforts to understand the interactions between genetic variants and treatments to improve care. Yang’s lab has made many other discoveries in the genetic basis for cancer and treatment risk and how they vary by ancestry. These include:

  • Treatment-related risk due to two specific inherited genetic factors contributing to hepatotoxicity in pediatric ALL that vary in prevalence based on ancestry, published in JAMA Network Open.

  • Ancestry itself is an independent factor contributing to differences in ALL treatment outcomes, published in JAMA Oncology. The study also showed that different ancestries correlated with higher risks of different ALL subtypes.

  • The inherited GATA binding protein 3 (GATA3) gene variant rs3824662 is correlated with worse minimal residual disease levels and poorer response to therapy, published in the Journal of the National Cancer Institute in high-risk B-ALL. 

  • That same GATA3 variant was more common in people with Hispanic or Native American ancestry, partially explaining the higher risk of relapse in patients with Philadelphia chromosome-positive (Ph)-like ALL experienced by these groups, published in Nature Genetics.

  • Patients with Hispanic ancestry appear to be at higher risk of ALL in the U.S. due to an inherited variant in the gene erythroblast transformation-specific transcription factor (ERG), published in Blood.

Making genetic predisposition tests accessible

Given the wealth of information on genetic risk for cancer, St. Jude launched the St. Jude Division of Cancer Predisposition, led by director Kim Nichols, MD, as part of the Department of Oncology. Nichols is charged with translating genetic predisposition research, such as that from Yang’s group, into actual clinical practice. 

“Most parents of children with cancer are really willing to do genetic testing on their children to understand why their child got cancer and also to determine whether their other kids might be at risk,” Nichols explained. “This is very important because we can now offer children at risk effective means of screening to pick up new tumors at their smallest and most curable stages. Outside of St. Jude, there are large racial differences in access to clinical care.”

“Our approach at St. Jude is to provide resources so that people can have access to genetic testing, genetic counseling, surveillance, and enrollment in clinical trials,” Nichols said. “But no other places are like St. Jude, where families incur no direct costs. It’s so much harder in the rest of the world to provide these services.”

Despite the increased access to cancer genetic testing that St. Jude offers, some parents still choose not to have their children evaluated. Indeed, Nichols and her team reported in a study published in Cancer Discovery that 15% of parents declined comprehensive genetic testing for their children with cancer. When trying to discern why this was the case, race/ethnicity was the only factor that was statistically associated with testing refusal. For many families, refusal was “passive,” meaning they did not firmly reject testing but instead didn’t end up testing because they didn’t attend appointments or respond to Nichols’ team’s requests to meet to discuss the testing.

“It is important that we learn more about why parents choose not to test their children,” Nichols explained. “Only then can we overcome some of the existing barriers and educate families about the potential pros and cons so that they can make informed decisions about whether or not to test their children.”

Genetic testing is becoming more common, especially with the rising popularity of consumer-facing genetic ancestry kits. Clinical testing is held to a higher standard than these services. However, genetic testing is similar to pre-existing clinical diagnostics, so it will likely be integrated into care in the near future. The greater challenge is translating that information into useful and accessible information for families.

The challenges of accessing genetic counseling

On the other end of the spectrum, genetic counseling is a highly needed but scarce resource. Most patients and their families do not have the scientific knowledge to understand and interpret the implications of their genetic testing results. St. Jude offers institutional genetic counseling as part of the Cancer Predisposition Division, free of cost to all patients with cancer and their families.

“We continue to see them and talk about their genetic testing results,” explained oncology genetic counselor LilyAnne Grieve. Nichols and her team are working with psychologist Katianne Sharp, PhD, and nurse researcher Belinda Mandrell, PhD, to understand how families understand and react to genetic test results for their children. They have found that parents of children who test positive for an underlying condition often experience distress, which can negatively impact their quality of life, as reported in their recent article published in JCO Precision Oncology.

“If we’ve identified an underlying cause for their tumor or cancer, we explain and encourage further surveillance and screening to catch cancers at the earliest, most treatable stages,” Grieve said. She further explained that St. Jude also offers testing to first-degree relatives of patients with an underlying cancer predisposition, such as their siblings and parents, at no cost.

But even for patients treated for free at St. Jude who receive the institution’s genetic services, access issues common to many outside the hospital arise when patients transition away to their local environment.

“When patients go home and face the barriers of their everyday lives, we can’t solve those problems,” Grieve said. “If they struggle to get transportation back here, or if they are food-insecure or have insecure housing or have lack of clean water access, they rightly prioritize the many bigger, more imminent life problems than knowing about their genetics.” 

One of the common themes of these barriers is a lack of access to services. 

“Not many states have enough genetic counselors,” said genetic counselor Passant Shaker, who works in hematology and helps patients with bleeding and clotting disorders. “If you’re in a rural area or have trouble accessing reliable transportation, then you may have trouble getting transportation to services or lack reliable internet access to participate in telemedicine, if that’s even offered by the genetic counselor.”

The answer to these problems is unclear, but there are some places to start. Currently, Medicare and Medicaid have a patchwork approach to genetic counseling services, with a handful recognized while others are excluded. Having the need for genetic counseling and testing recognized for more conditions by the largest payers in the U.S. health insurance system would be a huge boon to help establish more genetic counselors throughout communities.

Confronting the uncertainty of genetic test results

Even when patients or institutions, such as St. Jude, overcome these barriers to implement genetic testing and counseling, the lack of ethnic minority populations included in early genetic research has consequences. 

“When people of non-European ancestry undergo genetic testing, they are more likely to end up with uncertain results,” said genetic counselor Arti Pandey, who specializes in oncology. “Part of the reason is that when we do genetic testing and report results, it’s all in reference to an “ideal” genomic sequence, which is not associated with disease. This reference genomic sequence is derived from people of European ancestry.”

Therefore, people with non-European heritage often have many differences from the reference genome. Without sufficient data, it is challenging to know if these differences are meaningful in terms of being causative of cancer. These are, therefore, called variants of uncertain significance (VUSes).

“For some kids with specific symptoms, we might send out this larger panel, 500 to 600 genes,” Shaker offered as an example. “With each of those, we expect quite a few VUSes. We detect them, which can be nice, but often we’re not sure if it explains the condition or if it’s something that will get downgraded to negative or found not to be related to a condition in the future.”

The counselors sometimes must explain that the results are inconclusive after a family has gone through the work to be tested. The solution, while difficult in execution, is a simple idea: including more people of non-European ancestry in genetic studies.

“The representation of people of color in the genetics field is even lower than in the medical field in general,” Pandey said. “But I hope that soon, as the field becomes more inclusive, we will be able to use a reference genome that is more representative as we sequence people from more diverse backgrounds. There are several projects, including the 1000-Genomes Project and the Telomere-to-Telomere consortium, which may present us with an alternative to the current reference genome that has been derived from a few select individuals of a single ancestry 20 years ago.”

Addressing more inclusive genetics research to cure kids

Many institutions, including St. Jude, are developing clinical and translational genetics studies with population genetics in mind. The apparent need for genetic information from many populations to fuel these studies, especially clinical trials, is motivating organizations to recruit patients from more ethnically diverse backgrounds. 

The goal for these organizations is to cure children of pediatric illnesses so they can go on to live their fullest lives. Addressing racial differences has been part of the foundation of St. Jude since its inception. As part of the St. Jude mission statement reads, “No child is denied treatment based on race, religion or a family’s ability to pay.” 

“St. Jude is at the forefront of this research,” Yang concluded. “We want to improve cure rates across the entire spectrum of the population here in the U.S. and globally. We’re not just focusing on one population; we’re really focusing on kids from all backgrounds. We want all children — across the world — to benefit from our lifesaving research.”

About the author

Scientific Writer

Alex Generous, PhD, is a Scientific Writer in the Strategic Communications, Education and Outreach Department at St. Jude.

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