Cell division, the process of making new body cells, is a lifelong process. If you live to an average age, your body cells will divide about 10,000 trillion times. That’s one, followed by 16 zeros.

In any one of these divisions, just one mistake could be the beginnings of a tumor.

The TP53 gene: one of the most important genes in cancer research

I study molecular biology of pediatric adrenocortical tumors, a rare disease. And because of the strong association with a genetic defect in the TP53 gene, I’m also interested in this gene. The TP53 gene is responsible for monitoring cell division in your body. If a cell’s DNA is damaged or improperly copied, TP53 stops the cell from dividing. TP53 can correct the damage, prevent replication or send an apoptotic message, forcing the cell to die. In effect, the TP53 gene is the guardian of your genome.

We’re learning more about cancers and other conditions associated with TP53 mutations, including adrenocortical tumors (ACTs) and Li-Fraumeni syndrome. Our ACT research has also led to more information about Beckwith-Wiedemann syndrome.

“If a child has an adrenocortical tumor, many times, it’s because they have an inherited TP53 mutation,” says Gerard Zambetti, PhD, associate director of training and education for the St. Jude Comprehensive Cancer Center. “But there are other ways of getting to that same tumor type.”

But what about ACTs that are not showing germline mutations in the TP53 gene? This question left our team and the clinical team with a problem to solve. Our recent study published in the Journal of Clinical Oncology shows some ACT cases can also occur through a germline, or inherited, defect in chromosome 11p, and some others because of an unidentified molecular event. We still have a lot to do.

ACT and the Brazilian story

Years ago, Raul Ribeiro, MD, worked at St. Jude as a fellow. He then returned home to practice in Brazil and noticed a high incidence of ACT in children. He returned to St. Jude and began to organize the International Pediatric Adrenocortical Tumor Registry (IPACTR), collecting clinical and demographic data from patients with ACTs around the world.

Pediatric ACT is rare in the U.S., occurring in about 1 in 3 million children. In Brazil, pediatric ACT occurs 15 times more often. Dr. Ribeiro and his team identified that Brazilian patients having ACT were all associated with the same inherited TP53 mutation, even though the children were from different families.

I determined that this single mutation could be traced back several generations, and is the same for all Brazilian patients with this mutation. Because the registry developed at St. Jude included cases from Portugal and Spain that also share the same mutation as the Brazilian ones, it led us to the hypothesis that this mutation originated in Europe and spread to Brazil because of its colonialization history.

We learned that all of these families have the same founder mutation—some families have extensive cancers of all kinds, like Li-Fraumeni syndrome, where catastrophic mutations in TP53 result in a nearly 100 percent chance of developing cancer, sometimes multiple cancers, and usually at a young age—while other Brazilian families have little or no instances of cancer. This suggests other environmental or genetic interactions with the mutations may be the reason.

Through IPACTR, physicians around the world began sending medical and demographic information about their ACT patients. They also sent blood and tumor samples to give us more data for our research.

More screening and education needed

Because ACT can show up for quite different reasons, it’s important for patients and their families to find out the driver of that tumor.

A child with a TP53 mutation is at a higher risk for cancer. If a child is tested and found to have the mutation, then the child’s siblings and family members can also be checked for the same mutation. That information is critical in terms of future screening and surveillance.

Through whole-genome sequencing and other projects, we are learning more about the genetic events that lead to benign and aggressive cases. We discovered some of ACT’s drivers in cases without TP53 mutations. Our research and clinical team remain committed to investigating unknown instigators of this disease and furthering treatment options.

Indeed, our molecular analysis of adrenocortical tumors in the lab can inform clinical decisions regarding the effectiveness of specific treatments for patients.

Support and registry success

We encourage patients to enroll in our registry. It not only leads to discoveries, but it offers resources and support.

In addition, St. Jude hosts a two-day clinic twice a year. The St. Jude Collaborative Rare Endocrine Tumor Referral Clinic brings patients with adrenocortical tumors and their families to St. Jude to interact with our expert clinicians, Catherine Lam, MD, MPH, and Carlos Rodriguez-Galindo, MD. Patients and families from across the nation can come to St. Jude for consultations, medical exams, education and an introduction to tumor-related resources. St. Jude also has a specialized team for ACT surgery. Andrew Davidoff, MD,  offers ACT patients the option of having surgery here.

We still have a lot of work to do. Fortunately, we can now better understand the genetic events that trigger this rare disease and select treatment options because of those findings.