Cancer Predisposition: Power through the PCGP

Pinpointing future cancer risk

As an outgrowth of the Pediatric Cancer Genome Project (PCGP), St. Jude cancer patients are now offered clinical genomic testing of their tumor and healthy tissue (usually a blood or skin sample). Test results may reveal mutations that drive the growth of cancer cells, allowing doctors to select targeted therapies linked to better outcomes. The results may also uncover changes in genes that are inherited and lead to a higher risk of causing diseases such as cancer. These are called cancer predisposition genes.

“Patients who carry changes in cancer predisposition genes may develop additional cancers later in life or experience complications following certain cancer treatments, like radiation therapy,” says Kim Nichols, MD, St. Jude Cancer Predisposition Division director. “Unfortunately, we cannot prevent these cancers from happening. Our goal is to empower patients and parents to be aware of the signs and symptoms. In addition, through frequent screenings, we aim to catch new cancers early, when they are easier to treat and more likely to be cured.”

Test results showed Braxton had a rare genetic condition called Li-Fraumeni syndrome. This disorder is caused by a mutation in the TP53 gene. People with the condition are more likely to develop cancers in their brain, breasts, bones, blood, adrenal gland, muscles or connective tissue.

Rooted in research

Launched in 2010, the PCGP was the world’s most ambitious effort to discover the origins of childhood cancers and seek new cures. Researchers sequenced the genomes within blood samples of about 800 children with cancer.

Analyzing the treasure trove of data, scientists searched carefully for changes in 60 genes known to be linked to cancer predisposition. The most common hereditary disorders in the children in this study were hereditary retinoblastoma; neurofibromatosis type 1; familial adenomatous polyposis; and Li-Fraumeni syndrome, the genetic condition Braxton has.

St. Jude scientists add new genes to the list every year. For example, Nichols and Jun J. Yang, PhD, of Pharmaceutical Sciences and Oncology, found a new predisposition gene called ETV6 that is linked with a common form of childhood leukemia. Nichols, Yang and Charles Mullighan, MBBS, MD, also identified IKZF1, another leukemia predisposition gene, in children with B-cell acute lymphoblastic leukemia.

Early-catch benefits

Nichols joined St. Jude in the fall of 2014 to start the Cancer Predisposition Division and help translate the PCGP’s findings to the clinic. The program has grown substantially since then. Last year, Nichols and her team saw more than 1,100 patients, up from 400 patients in their first year.

In all, the team has evaluated more than 5,670 children with cancer and found underlying cancer predispositions in nearly 540 of them.

“About 10% of the patients with cancer predisposition who we monitor using radiology tests and blood work have developed new cancers,” Nichols says. “The vast majority of these cancers are picked up at a very early stage and have been successfully treated.”

St. Jude patients are followed for 10 years after they complete treatment, or until they turn 18, whichever is later. After Braxton’s initial therapy, he returned to Memphis every three months for comprehensive screening, which included ultrasound and full-body magnetic resonance imaging. After about 18 months, a scan showed that his brain tumor had returned. He had another surgery in November 2019. In January 2020, he began six more months of chemotherapy.

Each step of the way, a team of surgeons, oncologists and geneticists collaborated on his therapy in consultation with Nadine and Tim.

“We have to look carefully at the side effects of different treatment options,” Nadine says. “Radiation is not recommended due to his gene mutation. The doctors always hear our concerns about different chemotherapy alternatives and have already checked with the genetics team.”

Whole-family benefits

Genetic counselors with the Cancer Predisposition Clinic focus on the whole family. They study the patient’s disease and medical information in the family tree to find out if any family members, including future children, might have a higher risk of developing cancer.

“St. Jude is unique compared with other centers because we offer genetic testing and counseling to parents and siblings,” Nichols says. “Any siblings who have a mutation become our patients, and we monitor them closely. If they develop new cancers, we refer them to the appropriate treatment service team.”

Nadine and Tim decided to have their genomes tested to find out if they were also at risk. Fortunately, they learned that neither of them has the same mutation as their son.

“It was a huge relief to find out that my husband and I were negative,” Nadine says. “We want the opportunity to have another child without worrying about passing on a mutation.”

Toward brighter futures

St. Jude patients can opt into an ongoing study called Genomes for Kids. This project combines information on 150 cancer predisposition genes with clinical data to learn more about how the mutations influence cancer development and future outcomes. Nichols plans for this initiative to include results from several thousand children in the upcoming years.

“About 98% of DNA lies between our genes. It’s unclear what role that DNA plays,” Nichols says. “St. Jude researchers are working hard to see if changes in those poorly understood regions of the genome are associated with cancer development and hereditary predispositions to cancer. I am sure that they will be; we just don’t know enough about those areas yet.”

Now 3 years old, Braxton has a head full of strawberry blond curls. He is a bundle of energy and wants to understand how everything works. His favorite toy is a stuffed R2-D2, the droid robot from the movie Star Wars.

Besides the neuro-oncology experts who are part of his primary cancer treatment team, others at St. Jude are assisting Braxton. An occupational therapist helps him work on fine and gross motor skills to address left-side weakness. A speech-language pathologist helps him catch up on speech skills. And Braxton’s physical therapist gently reminds him that even though it’s fun to run down the hall and high-five everyone, it’s not a good idea while attached to an intravenous pole.

“Just like every toddler, Braxton is full of energy and can have tantrums about small things,” Nadine says. “But he sure loves all of the attention he gets at St. Jude. We’re glad they’re looking after him every step of the way.”

*Photos for this article were taken pre-COVID-19.

From Promise, Special Edition 2020