Genome sequencing initiative links altered gene to age-related neuroblastoma risk
Discovery of the first gene alteration associated with an indolent course of disease
- Date : 16 Mar 2012
- Topic : Head and neck cancers
Researchers have identified the first gene mutation associated with a chronic form of neuroblastoma that typically strikes adolescents and young adults. The finding provides the first clue about the genetic basis of the long-recognized but poorly understood link between treatment outcome and age at diagnosis. The study involved 104 infants, children and young adults with advanced neuroblastoma, a cancer of the sympathetic nervous system. Investigators discovered the ATRX gene was mutated only in patients age 5 and older. The alterations occurred most often in patients age 12 and older. These older patients were also more likely than their younger counterparts to have a chronic form of neuroblastoma and die years after their disease is diagnosed.
A new subtype of neuroblastoma with ATRX mutations
The findings suggest that ATRX mutations might represent a new subtype of neuroblastoma that is more common in older children and young adults. The work is from the St. Jude Children's Research Hospital – Washington University Paediatric Cancer Genome Project. The study appears in the March 14 edition of the Journal of the American Medical Association.
If validated, the results may change the way doctors think about this cancer. According to study co-author Richard Wilson, PhD, director of The Genome Institute at Washington University School of Medicine in St. Louis, doctors may need to think about different treatment strategies for patients depending on whether or not they have the ATRX mutation.
Until now there was no understanding of the basis of age-related risk, and no treatment has had an impact on the outcome
Neuroblastoma accounts for 7 to 10% of all childhood cancers and about 15% of paediatric cancer deaths. In about 50% of patients, the disease has already spread when the cancer is discovered. For patients whose disease has spread, age has long been a powerful but perplexing predictor of treatment outcome. Currently 88% of patients age 18 months and younger become long-term survivors, compared to 49% of those ages 18 months through 11 years and only 10% of patients age 12 and older.
According to Michael Dyer, PhD, a member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Early Career Scientist, and the study's corresponding author, the found mutation is associated with patients in the older age group, but it also identifies for the first time a subset of younger patients who turned out to have an indolent form of neuroblastoma.
According to Nai-Kong Cheung, MD, PhD, first author and head of the Neuroblastoma Program at New York's Memorial Sloan-Kettering Cancer Centre, researchers must now determine whether tumours with ATRX mutations behave the same way in both children and young adults, following a similarly indolent but often deadly course.
St. Jude investigators have begun screening the hospital's library of federally approved drugs looking for evidence of activity against neuroblastoma cells with the ATRX mutation. Availability of more targeted therapies would likely spur efforts for early identification of patients with the ATRX mutation who have a chronic form of neuroblastoma and are unlikely to benefit from current therapies.
The ATRX mutation is the latest discovery from this Paediatric Cancer Genome Project. The three-year project aims to sequence the complete matched normal and cancer genomes of 600 patients with some of the most poorly understood and aggressive childhood cancers. Investigators believe the findings will lay the foundation for a new generation of clinical tools.
Whole-genome sequencing study
This study involved whole-genome sequencing of the complete normal and cancer genomes of 40 neuroblastoma patients. To validate those results, an additional 64 neuroblastoma tumours were also sequenced. The normal and tumour tissue samples were all donated by Memorial Sloan-Kettering Cancer Centre patients.
The genome data from this and other published Paediatric Cancer Genome Project studies are available at no cost to the global scientific community at the Paediatric Cancer Genome Project Explore website. Click here to access Explore.
Researchers found the ATRX gene was mutated in 44% of the 32 patients with neuroblastoma age 12 and older. The gene was altered in 17% of the 54 patients 18 months through 11 years, although the changes were found only in patients age 5 and older. None of the 18 patients in youngest treatment group, those age 17 months and younger, had ATRX mutations.
ATRX mutations associated with neuroblastoma include deletions in the gene not found in other tumours
Although this is the first study linking changes in ATRX to neuroblastoma, mutations in the gene have been found in cancers of the pancreas, kidney and ovaries. In pancreatic neuroendocrine tumours, patients with ATRX mutations have a better prognosis while neuroblastoma patients with the altered gene fall into the age group with a poor prognosis. The ATRX mutations associated with neuroblastoma include deletions in the gene not found in other tumours.
Evidence in this study suggests ATRX mutations contribute to neuroblastoma cell survival in several ways, including alternative lengthening of telomeres (ALT). By lengthening the telomere, ALT contributes to the unchecked cell division that is a hallmark of cancer and likely makes cancer cells less vulnerable to chemotherapy or radiation therapy.
Researchers suspect ATRX is also involved in regulating the activity of other genes through epigenetic mechanisms that alter gene activity without changing the underlying DNA sequence. This is in keeping with previous discoveries at St. Jude that retinoblastoma and glioma cancer progression may be driven by epigenetic processes.
The research was funded in part by the Paediatric Cancer Genome Project, including Kay Jewelers, a lead project sponsor; the USA National Cancer Institute, the National Institutes of Health, the Catie Hoch Foundation, the Robert Steel Foundation and ALSAC.
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