From almost the moment she was born, Taryn Peterson has been an astute observer. The 4-year-old Colorado girl reacts to the world with curious glances and precocious responses. When her parents, Angela and Kenan, talk, she is quick to add her thoughts.
Taryn often wakes up and chats with her dolls, Elsa and Anna. These mornings of pretend and joy are a world away from how she spent her time last year.
Before her second birthday, Taryn began to have trouble sleeping. Her breathing was harsh, high-pitched and sometimes interrupted—a condition known as stridor. Her problems persisted after a sleep study and adenoid removal. Finally, partial paralysis on the left side of Taryn’s face prompted an MRI scan.
The scan revealed a tumor in her brain stem. Taryn had surgery right away to reduce the pressure on her brain.
“The doctors came in and told us that her tumor presented as DIPG, and that it was inoperable,” Angela says. “It was a whirlwind for all of us. We had no idea what we were going to do.”
Out of Sequence
DIPG, or diffuse intrinsic pontine glioma, is a tumor that forms in the brain stem. Fewer than 10% of children with the disease survive more than two years. Treatment consists of radiation therapy, often with chemotherapy. Given the growth pattern and critical location, surgery is not possible.
Scientists at St. Jude Children’s Research Hospital have studied DIPG for many years. In the last decade, findings from the St. Jude – Washington University Pediatric Cancer Genome Project (PCGP) helped us better understand the disease and its causes.
As part of the PCGP, scientists sequenced the genomes of normal and cancer cells in about 800 patients. Researchers then looked for differences in the DNA that lead to cancer.
The scientists learned that in DIPG and other gliomas in midline structures of the brain, specific mutations occur frequently in histone H3 proteins. Suzanne Baker, PhD, director of the Brain Tumor Research Division, along with Jinghui Zhang, PhD, St. Jude Computational Biology chair, and their colleagues led research that identified this mutation as histone H3 K27M.
“When the Pediatric Genome Cancer Project began, it wasn’t clear how different DIPG and other gliomas in children were compared to gliomas with similar features in adults,” Baker says. “These unexpected findings from sequencing showed not only that different mutations had been found in childhood gliomas than had been discovered in adults, but that some of these mutations had never been seen before in human cancer.”
The discoveries changed the way patients are diagnosed and selected for clinical trials. The findings also altered how clinicians evaluate treatment responses.
The Pediatric Cancer Genome Project gave us the next big breakthrough into the biology of some of these tumors that we could never have achieved if we hadn’t had that insight.
“He was so hopeful, so calm and explained everything really well. So, we said, ‘This is what we need to do,’” Angela says.
When the family arrived at St. Jude, they met with Tinkle; Amar Gajjar, MD, director of the Neuro-Oncology Division; and Paul Klimo, MD, of Neurosurgery. Although biopsy of DIPG tumors is rare, the physicians thought it was the best option for Taryn.
The surgery yielded surprising results.
Taryn’s tumor was not DIPG. It was an angiocentric glioma with a MYB-QKI fusion—a tumor with a much better prognosis. This allowed Taryn to be treated with proton therapy, which reduced exposure to more of her healthy brain cells.
“Sequencing assisted with the tumor diagnosis, as this type of fusion is found in most cases of angiocentric glioma,” Tinkle says. “Other more harmful mutations were not found in the tumor, including the histone H3 K27M mutation. When coupled with the histologic grade of the tumor, this allowed us to confirm that it was not DIPG.”
After the surgery, Taryn had six weeks of radiation to shrink the remaining tumor. She continues to have quarterly MRIs and is thriving a year after coming to St. Jude.
Into the Clinic
The PCGP continues to affect the diagnosis and treatment of patients at St. Jude. The project’s success laid the groundwork for the hospital’s clinical genomics program.
Genomic testing is now an option for all eligible St. Jude cancer patients. That led to the creation of the hospital’s Cancer Predisposition Program and several clinical trials.
“The Pediatric Cancer Genome Project gave us the next big breakthrough into the biology of some of these tumors that we could never have achieved if we hadn’t had that insight,” says Gajjar, who co-leads the SJMB12 study for children with brain tumors. “Over the past decade, those insights have rapidly been translated into clinical protocols, which hopefully will improve the cure rate for some of these tumors.”
Researchers used PCGP data to reveal that the most common malignant pediatric brain tumor—medulloblastoma—is not a single molecular entity, but a complex tumor with four major subgroups. That discovery was a surprise, because the tumors look similar under the microscope. Clinicians also had a hard time predicting outcomes for patients with medulloblastoma. Now we know that survival rates vary widely by subtype.
Today, specific therapies can be developed for each subgroup. The findings help direct the treatment of more than 500 patients enrolled in the SJMB12 study.
Through sequencing, G4K will allow researchers to learn more about how leukemia, lymphoma and solid tumors are formed and how they respond to treatment. All St. Jude cancer patients are eligible. The study also assesses patient and family opinions about genetic testing.
SJFAMILY explores why some cancers run in families and why certain people get more than one cancer. Scientists look for changes in sequenced genes to help answer these questions.
A Total Approach
Every child in the study has genomic testing of both normal tissue and leukemia cells to help guide treatment. Using genomic data from cancerous cells, researchers can identify mutations and target them with new chemotherapy agents. This practice of precision medicine uses genetics to tailor therapy.
With a goal to treat 1,000 patients, the study is the largest clinical trial ever run by the hospital and requires collaboration with other institutions. This study design helps researchers gather more data faster and share their findings.
“Genomics plays an important role in guiding therapy in this study,” says Hiroto Inaba, MD, PhD, of St. Jude Oncology, who leads the study. “We have the available technology. If we identify a patient as high-risk, we’re going to do whatever it takes to improve their outcome.”
Researchers worldwide have also incorporated findings from the PCGP into clinical trials. The results have led to National Cancer Institute initiatives to create therapies designed for children with cancer and to guide precision medicine.
*Photos for this article were taken pre-COVID-19.