Altered Gene Linked to Neuroblastoma in Youth

April 1, 2012 § Leave a comment

Neuroblastoma is a cancer of the sympathetic nervous system. It is a malignant tumor that develops from nerve system tissues, beginning in areas such as the adrenal glands, and can spread to the bones, bone marrow, liver, lymph nodes, skin, and around the eyes. It is most commonly diagnosed in infants, children and young adults, and is a very painful experience to live with.

Its cause has of yet been unknown, but researchers have recently identified the primary gene mutation responsible for a fatal form of neuroblastoma that is diagnosed in adolescents and young adults. This is the first clue as to the genetic basis of the link between treatment effect and the age of diagnosis.

A study from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP), appearing in the March 14th edition of Journal of the American Medical Association, suggests that mutations in the ATRX gene might be the source of a new subtype of neuroblastoma that is most common in older children and young adults.

The study was performed with 104 infants, children and young adults with highly developed neuroblastoma. Researchers discovered the ATRX gene was mutated in patients 5 years old and above. The alteration was apparent most often in patients who were 12 and older and these older patients were also much more likely that the younger patients to have a chronic form of neuroblastoma that causes death a few years after diagnosis.

If these findings are confirmed, they may change how doctors deliberate about this cancer.

The study’s co-author, Richard Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis, said, “This suggests we may need to think about different treatment strategies for patients depending on whether or not they have the ATRX mutation.”

Neuroblastoma is implicated in 7-10% of all childhood cancers and approximately 15% of pediatric cancer deaths. In over half of patients, the cancer has already spread before it can be discovered. For those in which the disease has spread, age has always been a prevailing predictor of treatment outcome. At this time, 88% of patients aged 18 months or younger become long-term survivors, compared to 49% of those aged 18 months through 11 years and only 10% of patients aged 12 and up.

Corresponding author Michael Dyer, Ph.D., member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Early Career scientist said, “Until now there was no understanding of the basis of this age-related risk, and no treatment has had an impact on the outcome. The mutation we found 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.”

Nai-Kong Cheung, M.D., Ph.D., first author and head of the Neuroblastoma Program at New York’s Memorial Sloan-Kettering Cancer Center, explains that the researchers now need to establish whether tumors with ATRX mutations behave the same ways in both children and young adults. St. Jude researchers have begun sifting through the hospital’s library of federally approved drugs in search of evidence of activity against neuroblastoma cells with the ATRX mutation. If they are able to find more targeted therapies, they could identify the patients with the ATRX mutation earlier.

This mutation is the latest discovery from the PCGP. Their project is predicted to last three years and the researchers believe the findings will provide an array of new clinical tools for the treatment of aggressive and poorly understood childhood cancers.

This particular study involved whole-genome sequencing and of the complete normal and cancer genomes of 40 neuroblastoma patients. An additional 64 neuroblastoma tumors were sequenced as well. The human genome includes a chemical alphabet that stretches more than 3 billion characters in length and contains the blueprints for building and sustaining human life.

Researchers found that the ATRX gene had 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 above. None of the 18 patients in youngest treatment group (17 months and younger) had ATRX mutations.

This is the first study to connect the changes in ATRX to neuroblastoma, but mutations of this gene have been found in other cancers. The ATRX mutations apparent in neuroblastoma include erasures in the gene not found in other tumours.

The study suggests that ATRX mutations contribute to neuroblastoma cell survival in many ways, counting a mechanism called alternative lengthening of telomeres (ALT). Telomeres are the DNA strands at the end of chromosomes that limits the number of times a cell can divide. In lengthening this strand, ALT contributes to the unchecked cell division characteristic of cancer. It also makes cancer less vulnerable to therapies such as chemotherapy and radiation.

The researchers also think ATRX is implicated in normalizing the activity of other genes through epigenetic mechanisms that modify gene activity without changing the DNA. This coincides with previous findings in studies performed at the St. Jude center.

Sources

“Altered Gene Linked to Fatal Neuroblastoma in Adolescents, Young Adults”. (March 15, 2012). Neuroscience News. March 18, 2012. http://neurosciencenews.com/gene-fatal-neuroblastoma-atrx-mutations/.

“Neuroblastoma”. (February 7, 2012). PubMed Health. A.D.A.M. Medical Encyclopedia. March 18, 2012. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002381/.

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