Serious fun: Addison Dunavent eagerly anticipates her checkups with Alberto Pappo, MD, who blends medical care with play and laughter.

Spitzoid Melanoma: Hide and Seek

St. Jude researchers find a new melanoma mutation in kids and adults.

By Jane Langille; Photos by Ann-Margaret Hedges

Six-year-old Addison Dunavent has a best friend whose birthday is one day after her own. They call themselves “eternal twins.” They certainly look like they could be sisters, but the truth is hidden in their genes.

From a young age, Addison had a growth on her left arm that looked like a hemangioma — a benign lump made of blood vessels that usually goes away on its own. But as she got bigger, the growth did too. When she was 4 years old, a dermatologist near her hometown removed it and sent it away for testing.

“We were shocked to learn it was spitzoid melanoma,” says Jesica Dunavent, Addison’s mom. “The second test confirmed the diagnosis, so our doctor contacted St. Jude Children’s Research Hospital right away. We were in Memphis within days.”

Thanks to St. Jude research, the discovery of a new gene mutation in spitzoid melanoma is helping kids like Addison receive the best treatment approach. The finding also represents an exciting new target for developing precision medicines to treat adult melanomas in the future.

Hiding in plain sight

In 2019, an estimated 96,480 new cases of melanoma will be diagnosed in the United States. A small fraction, less than 1%, will occur in children and adolescents.

Spitzoid melanoma, the most common pediatric melanoma, can range from slow growing to quite aggressive, but it is usually less aggressive than adult melanoma.

“The standard treatment is surgery followed by close observation,” says Alberto Pappo, MD, director of the Solid Tumor Division and co-leader of the Developmental Biology and Solid Tumor Program at St. Jude. “Most pediatric patients, 99%, are disease-free five years later.”

But here’s the catch: Spitzoid melanoma is difficult to spot.

A spitzoid tumor doesn’t look like a mole from the outside. It must be examined under a microscope to be diagnosed accurately.

“Spitzoid melanoma is also genomically different from other melanomas,” says Armita Bahrami, MD, of St. Jude Pathology.

Changes in six genes called ALK, RET, NTRK1/3, MET, ROS1 and BRAF are known to play a role in about half of spitzoid tumors, but for the other half, any other driver mutation has been unknown — until now.

 
 
Armita Bahrami

Pinpointing mutations:
Armita Bahrami, MD, of St. Jude Pathology says spitzoid melanoma doesn’t look like a mole. For that reason, it can be difficult to diagnose. 

An exceptional case

Pappo and Bahrami recently collaborated with Scott Newman, PhD, and Jinghui Zhang, PhD, of Computational Biology, on an unusually aggressive case of spitzoid melanoma in an 11-year-old boy. Their research was published in the journal Nature Medicine.

The child’s spitzoid melanoma started as a red growth on his ankle, but it grew and spread, even after treatments with surgeries and immunotherapies. He enrolled in the St. Jude Genomes for Kids study and scientists performed comprehensive clinical genome sequencing, including whole genome, exome and transcriptome sequencing on a sample of his tumor.

Whole genome sequencing identifies the exact order of all 3 billion building blocks that make up human DNA, the molecule that carries the master instructions for everything that happens in the body. Whole exome sequencing examines the small subset of DNA that holds the instructions for making proteins. Transcriptome sequencing pinpoints how genes are read to make proteins.

For the boy, the sequencing results revealed that a gene called MAP3K8 was fused to another gene. Since fusion genes are associated with several cancers, Newman reviewed published studies to understand what this fusion gene might be doing. He learned that it could activate a gene called MEK, known for fueling melanoma growth in adults. Further lab testing confirmed that the MEK gene was indeed activated in the boy’s tumor.

That insight meant the mutation was potentially treatable with a precision medicine. The patient was treated with anti-MEK and anti ERK drugs, and the cancer partially responded. This critical response indicated more secrets were hidden in the genomic data.

Jinghui Zhang

A team that included St. Jude Computational Biology Chair Jinghui Zhang, PhD, discovered that mutations in a single gene drive this type of melanoma. 

Fortune favors the prepared

Several months later, another MAP3K8 mutation turned up in a second patient with spitzoid melanoma. To learn how common it was, the St. Jude researchers expanded their search to screen tumors from 49 patients in the database.

“We were extremely surprised to discover MAP3K8 fusions in one-third of patients, and that they were the most common gene rearrangements,” Newman says. “We thought everything common would have been discovered already.”

Popular commercial screening tests use gene panels of the most commonly known genes associated with cancer.

“Without the whole genome and transcriptome sequencing through the St. Jude Genomes for Kids program, we would not have been able to make this discovery,” Newman continues. “Commercially available assays can only screen for the gene mutations they’ve been designed to identify. Mining a complete dataset is the gold standard for finding actionable insights.”

Commercial screening tests do not yet include mutations in MAP3K8, but some may soon, given this new finding.

Next, to determine the prevalence of MAP3K8 fusions in adult melanoma, the St. Jude researchers hunted for the rearrangements in data from the Cancer Genome Atlas project, an open cancer genomics database founded by the National Cancer Institute and the National Human Genome Research Institute.

“We found MAP3K8 rearrangements in seven cases, representing 1.5% of the total,” Newman says. “That sounds small, but given the large number of children and adults around the world who develop melanoma, that translates to many people who may be helped with precision medicines in the future.”

 

 

“Without the whole genome and transcriptome sequencing through the Genomes for Kids program, we would not have been able to make this discovery,” says Scott Newman, PhD, of St. Jude Computational Biology.

 
 

In good hands

St. Jude surgeons carefully removed Addison’s spitzoid tumor in August 2017. Since then, she has returned every three to six months to St. Jude where Pappo and the clinical melanoma team have kept a close eye on her progress.

Jesica measures Addison’s moles at home too. A second spot popped up and grew quickly, and it was also removed at St. Jude. It looked different from the first tumor but turned out to be another spitzoid melanoma.

Caleb Dunavent says his daughter has maintained a sweet relationship with Dr. Pappo throughout all her treatment.

“He sits down and plays Barbies with her,” Caleb says. “They talk like they’ve known each other forever. There’s nowhere in the world like St. Jude. We couldn’t ask for better care.”

From Promise, Summer 2019

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