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St. Jude Researchers Advancing Understanding of Molecular Basis of Rare Pediatric Cancer


NEW YORK (GenomeWeb) – Experts at St. Jude Children's Research Hospital are investigating the range of genomic mutations associated with rare, aggressive tumors that start in kids' adrenal glands, and collecting data in a registry to learn more about the molecular underpinnings of this cancer.

Adrenocortical tumors (ACT) occur in hormone-producing tissues of the adrenal glands, which sit on top of the kidneys. These cancers tend to occur in children but are rare. Pediatric ACT occurs in 1 in 3 million children. Around half the ACT cases have a germline TP53 mutation, and 15 percent have a germline alteration in chromosome 11p15. For the rest of the ACT patient population there is no known genetic mutation driving the tumor.

"For some reason that we don't know yet, the adrenal glands really care about this TP53 mutation," said Emilia Pinto, whose lab at St. Jude investigates the molecular biology of pediatric ACT and maintains the International Pediatric Adrenocortical Tumor Registry. Pinto explained that while the adrenal glands are developing in a child until age 4, these tissues are particularly prone to these tumors.

Although Pinto's lab focuses on researching the role of TP53 in ACT, there is still much unknown about the molecular basis of the disease. For example, why don't certain patients with TP53 mutations develop tumors while others do? How does the co-occurrence of TP53 mutations and alterations in other genes impact cancer prognosis? What other genes might be implicated in the disease? And, importantly, what biological mechanisms are at play in the subset of patients who don't appear to have any genomic drivers?

Pinto is looking for answers in her lab. Earlier this month she presented data from a study where a team of researchers performed whole-genome sequencing on tumor samples from 37 pediatric patients and identified germline mutations in phosphodiesterases (PDEs) genes in 22 percent.

Five of these patients carried a germline TP53 mutation and one patient had abnormal chromosome 11p15. "Our results suggest that germline mutations in PDE genes can contribute to pediatric adrenocortical tumorigenesis by collaborating with TP53 low-penetrant mutants and uniparental disomy of chromosome 11p15," Pinto and her colleagues reported in an abstract presented at the Endocrine Society's annual meeting.

In an earlier paper published in 2015 in Nature Communications, the researchers reported based on WGS analysis of the same 37 samples that 91 percent had loss of heterozygosity of chromosome 11p with selection against the maternal chromosome. IGF2 on chromosome 11p was overexpressed in all tumor samples, while 76 percent of tumors harbored TP53 mutations and loss of heterozygosity in chromosome 17. The researchers also found tumors harbored somatic mutations in ATRX and CTNNB1, and tumors that had TP53 and ATRX mutations were associated with more genomic abnormalities and a poor outcome. 

This analysis suggests that TP53 mutations likely cause ACT "by promoting chromosomal instability," Pinto's group wrote. And that loss of heterozygosity in chromosome 11p, which results in IGF2 overexpression, is an "early hallmark" of ACT.

Then, in a paper published in Pediatric Oncology in December 2017, Pinto and colleagues reported that TP53 mutations and Ki-67 labeling index (a marker for measuring cancer growth) were associated with prognosis. Nearly all the patients with lower measures Ki-67 labeling experienced three-year progression-free survival compared to less than half those with higher levels of this marker.

Within Pinto's lab, researchers are also studying in cellular and animal models how specific TP53 mutations impact the function of the gene. Based on the research her group has done so far, she said her team is getting better at being able to distinguish which tumors might require more or less intervention. "But we're still learning," Pinto said.

Before joining St. Jude in 2009, Pinto researched ACT in Brazil, where compared to the US, there are 15 times the number of cases of the disease, largely due to the TP53 p.R337H founder mutation. Although one out of 400 people in Brazil have this mutation, not everyone ends up getting ACT or other cancers.

"It's a public health problem because we don't know if the person is going to develop cancer or not, when, or what type of cancer people will develop," Pinto said. Babies born in Brazil are screened for this mutation, so doctors can continue to monitor those who have the mutation for cancer.

In the US there is no founder mutation, and families can have a variety of TP53 mutations, many of them showing up in the central part of the gene. TP53 mutations often point to a lethal cancer syndrome, called Li Fraumeni Syndrome, which increases the risk of a range of cancers in the family that manifest at a young age, including ACT.

Some families may not be aware that they're at increased risk for genetic mutations associated with ACT, and often it takes a child in the family to get the disease, before a familial mutation is identified. "Pediatric adrenocortical patients normally are a sentinel for a familial cancer syndrome, and genetic testing offered to the patient needs to be extended to the family members," Pinto said.

When a patient submits a sample, Pinto's lab first analyzes it for mutations in TP53. If a patient is positive for a mutation in this gene, researchers discuss the results with the family and offer them counseling and testing. "We try to inform patients, parents, and care providers what it means to have an adrenocortical tumor, what we can do for them, and what we can learn from tumors having or not having a TP53 mutation," she said.

The key to Pinto's molecular investigations into ACT, however, has been the International Pediatric Adrenocortical Tumor Registry, within which Pinto's group is able to collect information on cases from around the world. The registry has been around since 1992 and includes clinical data on around 400 cases. In 2000, researchers began collecting biological samples for molecular evaluations and has amassed around 200 samples so far.

Because ACT is so rare, Pinto noted that it's critical that doctors, families, and patients participate in the International Pediatric Adrenocortical Tumor Registry. "This registry exists to collect clinical demographics and biological samples for research that will improve our understanding of this disease and better guide treatment options, not just for the patient, but also for their families," Pinto said.