Patient to Pioneer

Last summer, 10-year-old Brendan Obioha traveled from Nigeria to Memphis, Tennessee, to receive life-saving cancer treatment at St. Jude Children’s Research Hospital. The young soccer player and math whiz has a rare blood cancer called biphenotypic leukemia.

The little boy arrived as a patient. But he quickly became a pioneer.

Brendan is one of the first children to enroll in a study that will lay the foundation for transforming childhood cancer therapy. That study is called Genomes for Kids.

Childhood cancer begins with a change—a mutation—in one or more genes. When it occurs only in a single cell of the body (known as a “somatic” mutation), the alteration may trigger the cell to grow uncontrollably and cause a tumor to form. Sometimes an alteration may be present in every cell of the body (known as a “germline” mutation). In this case, the mutation may increase the child’s risk of developing cancer later in life. St. Jude research has shown that at least 8.5 percent of St. Jude cancer patients have germline mutations, which can be passed down through families.

The St. Jude-Washington University Pediatric Cancer Genome Project, which began in 2010, compared the genomes (the complete genetic blueprint) of both cancerous and normal cells from more than 800 children. That project provided important insights into some of the toughest childhood cancers. In the project’s second phase, St. Jude developed new lab and computer facilities that would enable scientists to do clinical testing, analyze data and interpret its significance.

This comprehensive genomic analysis is something that you can only do at St. Jude. And this vision for the future is what makes St. Jude unique.

Kim Nichols, MD, Cancer Predisposition Division director

“The efforts to establish this one-of-a-kind clinical sequencing platform required a concerted effort over 18 months by molecular pathologists, computational biologists, computer science experts, pediatric oncologists, clinical geneticist, genetic counselors and medical ethicists,” says James R. Downing, MD, St. Jude president and chief executive officer.

“We are thrilled that we’ve laid the groundwork for moving this technology into the clinic,” adds Jinghui Zhang, PhD, chair of St. Jude Computational Biology. “Our goal is to determine how best to tap its potential to improve patient care.”

That’s where Brendan comes in.

While he undergoes cancer treatment, he is also taking part in Genomes for Kids. This research study uses a technology called next-generation sequencing to pinpoint the specific gene changes that cause cancer to develop. Armed with those details, scientists will be able to understand more about why the tumors formed and learn how to treat them better.

“This gives us an opportunity to apply the kind of information we have learned from the Pediatric Cancer Genome Project to the actual clinic,” explains Kim Nichols, MD, director of the new St. Jude Hereditary Cancer Predisposition Clinic.

Kim Nichols, MD, with patient Brendan Obioha — After completing cancer treatment, Brendan (pictured with Kim Nichols, MD, Cancer Predisposition Division director) anticipates returning to the soccer field and his school’s robotics club

St. Jude scientists expect Genomes for Kids to be the first step in a clinical genomics effort that will usher in a new day—an entirely novel way of treating children with cancer and other life-threatening diseases.

All St. Jude cancer patients are now offered the opportunity to have their tumor and normal cell genomes sequenced as part of their routine workups. Participants in Genomes for Kids agree to let researchers isolate DNA from part of their tumor—or bone marrow in Brendan’s case—to look for changes in 565 cancer-related genes.

To identify germline changes that could reveal whether the risk for cancer was inherited, St. Jude scientists currently look for alterations in 63 genes in the child’s healthy tissue. These genes have been commonly associated with childhood cancer predisposition. The number of genes examined will increase in the coming years.

Surprising number of young cancer patients are predisposed to the disease

When cancer is found in a young patient, parents often ask: “Why my child?”

New evidence suggests that some children may be born at an increased risk of developing cancer early in life. In a landmark study from St. Jude and Washington University in St. Louis, investigators closely examined the genetic makeup of 1,120 children with cancer. They found that 8.5 percent—nearly one in 10—of those patients was born with genetic changes or mutations that increased their cancer risk.

These changes, called germline mutations, are found in the DNA of every cell, not just tumor cells. Such mutations were known to exist, but their frequency was a mystery.

“The study marks a turning point in our understanding of pediatric cancer risk and will likely change how patients are evaluated,” says James R. Downing, MD, St. Jude president and chief executive officer.

These mutations can be used to help guide treatment and advance precision medicine. In some cases, entire families may benefit from genetic testing and counseling. St. Jude is now offering comprehensive genetic testing to its cancer patients as part of the Genomes for Kids clinical research study. This study is designed to lay the groundwork for transforming childhood cancer therapy through genomic sequencing.

If a mutation associated with increased cancer risk is found, children and families are referred to the St. Jude Hereditary Cancer Predisposition Clinic. There, a team of medical specialists work with families to understand and better manage their cancer risks.

The study, part of the Pediatric Cancer Genome Project, was published recently in the New England Journal of Medicine.

"The thing that is unique about St. Jude is the technologies we’re using,” Nichols says. “Other institutions that are doing genomic analysis are doing something called whole-exome sequencing, which only looks at a slice of the human genome—about 1 to 2 percent. At St. Jude, when you have the tumor tissue tested, we’re also doing whole-genome sequencing and RNA sequencing. We’re looking at every part of the entire human genome, as well as every part of what is known as the ‘transcriptome,’ which is the RNA blueprint from which proteins are made. It’s a comprehensive way to investigate the tumors for as many genetic abnormalities as possible."

St. Jude uses three kinds of sequencing

to pinpoint as many genetic abnormalities as possible:

1

Whole -Genome Sequencing

The genome includes the complete set of instructions to assemble and sustain humans. The genome is encoded in the DNA molecule carried in almost every cell. Whole-genome sequencing involves determining the exact order of the 3 billion nucleotides that make up human DNA.

2

Whole-exome Sequencing

The exome comprises 1% to 2% of the genome and contains the more than 20,000 genes that encode the building blocks for life.

3

RNA Sequencing

This procedure reveals which genes are being expressed and at what level.

Brendan’s mom, Anita, says the possibilities are intriguing.

“This study is supposed to help to find out why cancer happens,” she says. “I signed up to have them test the normal as well as cancerous cells. I want to know if the cancer was passed down or if we could have it in the future. I want to know why the genes change, what particular gene changes might be in our family. I’m really curious.”

As part of the study, scientists are trying to determine the best ways to share testing results with families. After Brendan’s genomic sequencing is complete, a doctor and genetic counselor will meet with his family to explain the results and how they may affect Brendan and his family. If he has a germline mutation that increases cancer risk, he and his family will receive care and counseling through the Hereditary Cancer Predisposition Clinic.

If we don’t do these studies, there’s no way we can move forward.

Anita Obioha, Brendan's mother

Nichols envisions creating a precision medicine pipeline, in which mutations are discovered in a child, a team of scientists identifies drugs that target those particular alterations, and the treatment is provided to the child.

“This is the bedside-to-bench-to-bedside approach,” Nichols says. “This comprehensive genomic analysis is something that you can only do at St. Jude. And this vision for the future is what makes St. Jude unique.”

Brendan Obioha with his mother, Anita — “I would love it if my child’s illness could help the doctors find ways to make it easier to treat other children,” says Anita Obioha about the Genomes for Kids study.

The Genomes for Kids research study is designed with tomorrow’s patients in mind.

“We tell families that this study will not necessarily influence the treatment of their children today, but may be helpful for children in the future,” Nichols says.

Anita says she hopes Brendan’s participation may benefit others.

“Children don’t deserve to have cancer,” she says. “I want to help the world in any way I can. I would love it if my child’s illness could help the doctors find ways to make it easier to treat other children.

“If we don’t do these studies,” she continues, “there’s no way we can move forward. That’s the way I see it.”

Editors note: Brendan Obioha lost his battle with cancer June 3, 2016.

More information about the Genomes for Kids research study

From Promise, Winter, 2016

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Patient to Pioneer

Surprising number of young cancer patients are predisposed to the disease

St. Jude uses three kinds of sequencing

to pinpoint as many genetic abnormalities as possible: