Vials containing DNA samples from studies of the genetic risk for cancer at the Cancer Genomics Research Laboratory. Photo courtesy of the National Cancer Institute.
UC San Francisco physician-scientists have developed a test that can predict how patients with juvenile myelomonocytic leukemia (JMML) will respond to treatment, and may also be able to identify patients who are likely to recover spontaneously with little to no treatment. The researchers are currently optimizing the test for more routine clinical use in the United States.
JMML is an aggressive leukemia that strikes approximately 50 children in the United States each year, typically under the age of four. The only known treatment is bone marrow transplant, an intensive therapy with serious long-term side effects. Unfortunately, transplants are only effective in half of all patients, with the other 50 percent relapsing within a few years. On the other hand, in rare cases, children with JMML have been known to spontaneously go into remission, but until now, no one had been able to predict at diagnosis which patients will have these radically divergent outcomes.
In a new study, published December 19, 2017 in Nature Communications, UCSF oncologists have discovered that epigenetic annotations of the genome — chemical “tags” that affect whether, how, and when particular genes are expressed — can predict how children with JMML will respond to treatment. Using these tags as biomarkers could for the first time allow oncologists to make more informed treatment plans for these children. However, the study also emphasizes that many patients are unlikely to ever benefit from currently available treatments, and highlights a pressing need to develop new targeted therapies.
“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said senior author Mignon Loh, MD, a UCSF Benioff Chair of Children’s Health and the Deborah and Arthur Ablin Endowed Chair in Pediatric Molecular Oncology. Loh, who is a member of the Helen Diller Family Comprehensive Cancer Center at UCSF, directs the UCSF JMML clinic at UCSF Benioff Children’s Hospital San Francisco.
Loh emphasized the collaborative nature of the work, which was conducted in partnership with JMML researchers in Germany, who shared a subset of their own data as a validation dataset for the UCSF team, and who are publishing their own findings in the same issue of Nature Communications.
“Working with our German colleagues to use their data to validate our findings in a blinded fashion added an independent level of rigor to our results, and really strengthens the findings,” Loh said.
DNA Methylation Predicts Relapse Risk Following Bone Marrow Transplant
Previous studies by the UCSF team had shown that the number of mutations in a handful of key genes could help predict long-term outcomes for JMML patients, but in many patients, mutations alone did not seem able to explain why patients were having such different responses to treatment.
“We would see two different 2-year-olds with the exact same mutation, but one patient would relapse shortly after transplant, while the other would be cured, " said Elliot Stieglitz, MD, an assistant professor of pediatric hematology/oncology at UCSF and member of the Helen Diller Family Comprehensive Cancer Center who trained in Loh’s lab during his fellowship and is one of three co–first authors on the new study.