INFANT LEUKEMIA GENETICS

Why do babies just a few months old sometimes develop cancer when they have not lived long enough to accumulate a critical number of cancer-causing mutations? Researchers have come one step closer to solving that puzzle.

Results from a study published online January 10 in Leukemiasuggest that these babies inherit rare genetic variants from both parents that, by themselves, would not cause problems, but in combination put the infants at high risk for leukemia.

Infant leukemia is rare and sporadic; there are only about 160 cases reported each year in the United States. The prognosis is poor in infants, who have a 5-year event-free survival rate of around 50%. In older children, the results are excellent.

This research on infant leukemia could eventually lead to improvements in treatment, and possibly even prevention, said senior author Todd Druley, MD, PhD, assistant professor of pediatrics in the division of hematology and oncology at the Washington University School of Medicine in St. Louis, Missouri.

Identifying the Genetic Damage

Dr. Druley and his colleagues conducted exome sequencing on noncancer cells taken from 23 infants with leukemia and their mothers. They also sequenced the DNA of 25 healthy children who had no family history of pediatric cancer.

Sequencing showed that infants with leukemia were born with an excess of damaging changes in genes known to be linked to leukemia, Dr. Druley explained. "For each child, both parents carried a few harmful genetic variations in their DNA, and just by chance their child inherited all of these changes."

The researchers note that it is unlikely that these inherited variants are the only factor leading to the development of the disease. Infant leukemia is a distinct condition with evidence of both genetic and environmental causes.

Dr. Druley cautioned that it is "absolutely too early to make any clinical recommendations" from these data.

Theoretically, this information can help identify infants at risk, but Dr. Druley emphasized that they are not advocating any type of systematic screening program at this time. Only 2% of the genome of a small cohort of patients has been sequenced, and there is a "massive amount" of additional information necessary to suggest any clinical utility.

The first step is to functionally test frequent variant combinations of genes from these infants, he pointed out. Right now, the team is in the process of collecting skin cells that can be reprogrammed into stem cells and differentiated into hematopoietic progenitors. These will be used in functional testing and the targeted editing of specific genes. "This will allow us to study the patient's actual germline variability," he told Medscape Medical News.

Because the condition is very rare and a family history of cancer is not part of the equation, it will be difficult to determine which children to screen. Parents will need to know about their own genes to justify screening an infant.

"I expect that parents will have the option, in the near future, of undergoing large-scale sequencing prior to having children," Dr. Druley noted, because the use of genomic assays is increasing in clinical medicine. However, "that is far downstream and nothing we are advocating at this time."

Finding the genetic basis for a disease brings with it the hope of new and more effective therapies. Currently, more than half of these infants succumb to their illness because they fail to respond to therapy; that hasn't changed substantially since the advent of hematopoietic stem cell transplantation 25 years ago.

"A better understanding of the factors driving these cancers will surely improve our ability to treat them," he said. "But in this case, therapy becomes tricky because agents targeted against these genes could have consequences well beyond the cancer, since the variants are germline."

A better option might be to genetically engineer the patient's own cells before autologous transplantation, but that's also a long way off, he said. "In the short term, I'm hoping that we can refine which genes act in concert to allow leukemia to develop in the first place. I bet that will have broader implications on leukemia biology, and perhaps hematopoietic development."

Deciphering the Genome

Dr. Druley pointed out that for other complex childhood illnesses, such as asthma, seizures, and congenital heart disease, the focus is on multiple inherited germlines and de novo variants with or without epigenetic or environmental influences.

But cancer is different. "Sequencing adult cancer genomes demonstrates an average of 2 to 8 somatic driver mutations per cancer," he told Medscape Medical News. "Yet, enormous amounts of exome and genome sequencing in multiple pediatric cancers continue to demonstrate that the prevalence of somatic mutations is too low to account for the incidence of these diseases."

"It's not inconsequential, but it's not the whole story either," Dr. Druley added.

Most cases of infant leukemia are accompanied by MLL rearrangements, with very few somatic mutations, but less is known about genetic variations in cases lacking MLL translocations. Generally, infants without MLL rearrangements have better outcomes, as well as a "unique expression profile," than infants with MLL rearrangements and childhood B-precursor acute lymphocytic leukemia.

In their study, Dr. Druley and colleagues sequenced DNA from infants without MLL rearrangements. Most had approximately 3 to 5 genes harboring deleterious sequence changes.

"One could speculate that the total amount of 'genetic burden' required to cause a normal cell to become a cancer cell is equivalent for most cancers," explained Dr. Druley. "But the manner in which that genetic burden is accumulated is qualitatively different between infants/children and adults who acquire their burden over a lifetime."

"It will be interesting to see if a similar pattern of enrichment for deleterious variation is found in different sets of candidate genes in other pediatric cancers," he added.

The research was funded by the Children's Discovery Institute at Washington University School of Medicine and St. Louis Children's Hospital, the National Institutes of Health, the National Cancer Institute, Alex's Lemonade Stand "A" Award, the Hyundai Hope Award, the Eli Seth Matthews Leukemia Foundation, and the Children's Cancer Research Fund. The authors have disclosed no relevant financial relationships.

Leukemia. Published online January 10, 2014. Abstract