Advances in childhood cancers
Whole-genome sequencing has helped identify cancer subtypes and potential targets for therapy
Article first published online: 19 SEP 2012
Copyright © 2012 American Cancer Society
Volume 118, Issue 19, pages 4639–4640, 1 October 2012
How to Cite
Printz, C. (2012), Advances in childhood cancers. Cancer, 118: 4639–4640. doi: 10.1002/cncr.27827
- Issue published online: 19 SEP 2012
- Article first published online: 19 SEP 2012
Editor's note: This is Part 2 of a 2-part series on recent advances in pediatric cancers. Part 1 was published in the September 15th issue.
Medulloblastoma, the most common malignant childhood brain tumor, strikes approximately 400 children and adolescents annually in the United States. Recently, scientists have discovered new clues that will help them target specific genetic missteps in some subtypes of the disease.
Researchers have identified 4 main medulloblastoma subtypes: the wingless (WNT) subtype, the sonic hedgehog subtype, and subtypes 3 and 4. The WNT subtype has the best prognosis, with a survival rate of approximately 90% in a disease with an average survival rate of about 70%, says Giles Robinson, MD, a research associate in the oncology department at St. Jude Children's Research Hospital in Memphis, Tennessee. In contrast, just 60% of patients with subtype 3 medulloblastoma are alive 3 years after diagnosis. The other 2 subtypes fall in between in terms of prognosis.
Patients in the WNT subtype group (named for the pathway disrupted in the tumor subtype) tend to be female and slightly older. They also represent only approximately 10% to 15% of all medulloblastoma patients. Currently, all patients with medulloblastoma undergo surgery to remove the tumor and then receive chemotherapy and radiation. There is no risk stratification, except for those patients in whom the disease has spread or who have residual disease, in which case they are treated with a higher dose of radiation.
As part of the St. Jude Children's Research Hospital- Washington University Pediatric Cancer Genome Project, researchers recently sequenced the complete and normal genomes of 37 patients with medulloblastomas. They also examined tumors from 56 additional patients for the same alterations. Their findings reported that a high percentage of patients with WNT-subtype medulloblastoma had mutations in the DDX3X gene.1 Other genes, including CDH1 and PIK3CA, also were linked to this subtype. In addition, researchers demonstrated that subtypes 3 and 4 often had alterations in genes (EZH2 and KDM6A) that impact cell maturation and could keep cells dividing.
Another study by researchers from Stanford University and the Broad Institute of MIT and Harvard in Boston, Massachusetts, found similar mutations after examining DNA from 92 patients with medulloblastoma and comparing it with DNA from matched blood samples from the same patients.2 “With multiple, independent groups getting the same results, with slightly different information, we can combine the numbers to really understand it,” Dr. Robinson says.
The Challenge of Classification
Approximately two-thirds of patients with medulloblastoma now survive 5 years past diagnosis, but many survivors experience long-term physical and cognitive side effects from their treatment. Furthermore, the tumors frequently grow against the brain stem, and removing them can be quite challenging. They also have the propensity to spread throughout the brain and spinal cord. Generally, radiation is used to treat these cases, but it is not safe to irradiate children aged younger than 3 years; consequently, they are at a significant disadvantage in terms of survival, says Dr. Robinson.
If drugs can be tailored to a patient's unique genetic profile, then physicians can begin to reduce treatment side effects as well as improve survival, says Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford School of Medicine and senior author of the Stanford study.2 He adds that drugs are already in the pipeline, including a phase 2 clinical trial for agents that target the sonic hedgehog signaling pathway. He anticipates that in the next 2 years physicians may have a new set of compounds to offer children based on these genomic studies.
Another challenge is being able to effectively classify 100% of the tumors into the proper subtype. The gold standard for classification requires freezing the tumor in liquid nitrogen and having a large amount of the tumor sample, but that does not always happen. It is easier for the surgeon to pack the tumor in paraffin blocks, which is not as ideal. “The last thing you want to do is open a trial and say half of you don't qualify because we can't figure out what subtype you are,” Dr. Robinson says. However, a pathologist at St. Jude has developed a method, using other RNA extraction tests, in which 3 of the 4 medulloblastoma subtypes can be accurately diagnosed.
Leukemia Subtypes and Targets Identified
Meanwhile, other researchers are searching for ways to further improve cure rates for patients with acute lymphoblastic leukemia (ALL) while reducing radiation for the disease. Antileukemic agents and improved supportive care have led to a 5-year survival rate of greater than 85% for pediatric ALL patients in developed countries, says Ching-Hon Pui, MD, chair of the department of oncology at St. Jude. Supportive care has improved dramatically.
New developments in next-generation, whole-genome sequencing have led to a further understanding of leukemogenesis, drug resistance, and host pharmacogenomics. As with medulloblastoma, these advances have helped to identify new leukemia subtypes and potential targets for therapy. Recent studies have identified inherited polymorphisms, such as ARID5B, IKZFI, CEBPE, and CDKN2A, that are associated with the risk of childhood ALL in different racial and ethnic groups, says Dr. Pui.
His goal is to reduce prophylactic cranial radiotherapy for patients with ALL, because studies have shown that it can cause many problems, including secondary cancers and cognitive impairment. Physicians at St. Jude stopped using prophylactic cranial irradiation to treat patients with ALL 14 years ago. During that time, of the approximately 800 patients with ALL treated, they have not lost a single patient from a disease recurrence (11 of the patients ultimately received radiation for recurrences and remained in remission at the time of last follow-up).
Dr. Pui adds that there is no safe dose of cranial irradiation. He cites the ALL-BFM study, which found that the cumulative risk of second neoplasms from cranial irradiation reached 1.7% at 15 years after induction and was expected to increase with longer follow-up.3 “Many investigators still strongly believe in using radiation, but it's really not necessary,” he says.
Life Study Follows Survivors for Many Years
Some 2000 long-term survivors of childhood cancer have been evaluated as part of the St. Jude Life Study, providing important clues about their health. Many of these patients are now in their 40s, 50s, and 60s. The hospital coordinates travel arrangements and pays for lodging and meals as well as travel if patients live more than 300 miles away.
“We have found cognitive problems, people who are not walking well, and breast cancers in some patients treated with radiation,” says Dr. Pui. “We use that information to improve future generations of protocols.”
A typical visit takes 2 to 3 days, and patients undergo basic health examinations, blood tests, X-rays, and other medical tests depending on the treatment they underwent as children. They also meet with a social worker and are examined for cardiac function, muscle strength, and flexibility as well as overall physical performance. Most patients are seen once every 2 years.