Sun damage causes genetic changes that predispose children and adolescents to melanoma

St. Jude Children’s Research Hospital—Washington University Pediatric Cancer Genome Project has identified the genetic basis of three pediatric melanoma subtypes; findings could lead to better diagnosis and treatment.

The St. Jude Children’s Research Hospital—Washington University Pediatric Cancer Genome Project found that melanoma in some adolescent and adult patients involves many of the same genetic alterations and would likely respond to the same therapy. The research appears in the March issue of the Journal of Investigational Dermatology.

The similarities involved adolescents with conventional melanoma tumors and included the first genetic evidence that sun damage contributes to melanoma in children and adolescents as well as adults. The findings stem from the most comprehensive analysis yet of the genetic alterations responsible for pediatric melanoma, which is the most common skin cancer in children and adolescents.

“This study shows that unlike many cancers, conventional melanoma is essentially the same disease in children and adults. That means we need to make it easier for adolescents to access promising therapeutic agents being tried in adults,” said co-corresponding author Alberto Pappo, M.D., a member of the St. Jude Department of Oncology. “These results also underscore the importance of starting sun protection early and making it a habit for life.”

Researchers also identified distinct genetic alterations associated with other pediatric melanoma subtypes, including those associated with large congenital nevi (CNM) and spitzoid tumors. The alterations include a mutation that might help identify spitzoid patients who would benefit from aggressive therapy as well as those who could be cured with less intensive treatment.

“Until now the genetic basis of pediatric melanoma has been a bit of a mystery,” said co-corresponding author Armita Bahrami, M.D., an assistant member of the St. Jude Department of Pathology. “With this study, we have established the molecular signatures of the three subtypes of this cancer, signatures that have implications for diagnosis and treatment.”

The National Cancer Institute (NCI) estimates that melanoma is diagnosed in 425 U.S. residents age 19 and younger each year. While the cancer remains rare in young people, the incidence has risen about 2 percent annually in recent decades, primarily in those ages 15 to 19. That age group makes up the majority of current pediatric melanoma patients. For the 75 percent of pediatric patients whose disease has not spread, long-term survival rates now exceed 90 percent.

“We were surprised to see that so many of the pediatric melanomas had genetic changes linked to UV damage,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This in-depth look at the genomics of pediatric melanoma is extraordinarily important for diagnosis and for selecting treatments that give young patients the best chances of a cure.”

This study included 23 melanoma patients ranging in age from 9 months to 19 years old. Researchers used whole genome sequencing and other techniques to compare the normal and tumor genomes of patients with three different types of melanoma for clues about the genetic alterations that underlie their disease. The genome is the blueprint for life that is encoded in the DNA found in almost every cell.

The group included 15 patients with conventional melanoma. Unlike many pediatric cancers, their tumors included numerous genetic alterations, more than any of the childhood cancers studied so far by the Pediatric Cancer Genome Project. More than 90 percent of the tumors had genetic changes consistent with damage caused by ultraviolet light. More than 60 percent of the tumors had mutations in the BRAF oncogene, the PTEN tumor suppressor gene or the promoter region of a gene calledTERT. The same alterations are found in melanoma in adults and promoted the unchecked cell division and other changes that are hallmarks of cancer.

In contrast to conventional melanoma, the three patients with the CNM subtype had mutations in theNRAS oncogene and no defects in PTEN. The patients all died of their disease.

In comparison, cancer caused the death of just one of the five spitzoid melanoma patients studied. That patient was also the only one with widespread disease and the only one whose tumor had aTERT promoter mutation. TERT promoter mutations are common in conventional melanoma. The finding has led to a larger study to determine if TERT promoter mutations can serve as a marker for spitzoid tumors that are destined to become clinically aggressive. The results are expected soon.

The Pediatric Cancer Genome Project was launched in 2010 to use next-generation, whole genome sequencing to advance understanding, diagnosis and treatment of some of the most aggressive and least understood childhood cancers. The complete normal and cancer genomes of 700 young cancer patients were sequenced during the project’s first three years.

The first authors are Jinghui Zhang, Ph.D., a member of the St. Jude Department of Computational Biology, and Charles Lu, Ph.D., Washington University School of Medicine. The other authors are Panduka Nagahawatte, John Easton, Seungjae Lee, Zhifa Liu, Marcus Valentine, Fariba Navid, Heather Mulder, Ruth Tatevossian, James Dalton, James Davenport, Zhirong Yin, Michael Edmonson, Michael Rusch, Gang Wu, Yongjin Li, Matthew Parker, Erin Hedlund, Sheila Shurtleff, Susana Raimondi, Bhavin Vadodaria, Donald Yergeau, William Evans, David Ellison, Stanley Pounds, Michael Dyer and James Downing, all of St. Jude; and Li Ding, Matthew Wyczalkowski and Elaine Mardis, all of Washington University.

The research was funded in part by the Pediatric Cancer Genome Project, including Kay Jewelers, a lead sponsor; grants (CA21765) from the NCI at the National Institutes of Health (NIH); grants (EY014867, EY018599, CA168875) from NIH; and ALSAC.