US scientists have found that mutations of a gene called anaplastic lymphoma kinase (ALK) were behind most incidences of hereditary neuroblastoma, a rare and deadly childhood cancer, and they also discovered that the same mutations played an important role in high risk forms of non-inherited incidences of the disease, which are more common.
The study was the work of first author Dr Yael Mossé, a pediatric oncologist at the Children’s Hospital of Philadelphia, Pennsylvania, and colleagues and is published in the 24th August advance online publication of the journal Nature.
“This discovery enables us to offer the first genetic tests to families affected by the inherited form of this disease,” said Mossé.
She explained that because there are drugs already being developed that target the same gene in adult cancers, it shouldn’t take as long to test treatments for childhood neuroblastoma using these drugs as it would with new drugs.
Neuroblastoma, a very rare disease, but the most common solid cancer of early childhood, is rarely found in children over 10 years old. It accounts for 7 per cent of all childhood cancers but is disproportionately responsible for 15 per cent of childhood cancer deaths due to its aggressive nature. About 600 new cases of all forms of neuroblastoma occur every year in the US.
The disease can be inherited, but until this study the genetic factors involved were largely a mystery to scientists.
Belying its name, neuroblastoma is an “extra-cranial” cancer, ie it forms outside of the brain, wherever there are clusters of developing nerve fibres, or nerve-like fibres (such as in the medulla of the adrenal glands). Most neuroblastomas start in the abdomen, while the rest start in the chest, neck, pelvis, or more rarely, in the spinal cord.
Because neuroblastoma is so rare, and inherited forms of the disease are even rarer, Mossé and colleagues used family data collected from all over the world to examine the genes of 20 families with a history of neuroblastoma. The data came from the laboratory of Dr John M Maris, senior author of the study and director of the Center for Childhood Cancer Research at he Children’s Hospital of Philadelphia. The lab holds the world’s largest collection of neuroblastoma tissue samples.
The researchers performed genome-wide scans of the DNA of 10 families with a history of neuroblastoma and for which there was the most information.
The first thing they found was that a region of chromosome 2 was linked to the disease, and then when they looked at the DNA sequences in that region they found that 6 of 8 families with at least three cases of the disease had extra copy mutations of a gene called anaplastic lymphoma kinase (ALK). The other two families had mutations in a different gene, the PHOX2B gene, which has been found before in a small number of inherited cases of neuroblastoma.
The authors concluded that:
“Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.”
“This is a very important discovery,” said Maris, because “it not only helps us understand the genetic roots of this terrible disease, but also has led to dramatically new ideas for curative therapy.”
Mossé explained that:
“This finding means that it is possible to offer simple, non-invasive screening for patients with a family history of neuroblastoma.”
She said an ultrasound or urine test could be used to monitor children with an ALK mutation, and aid early detection of potential neuroblastomas.
“As we increase our knowledge of ALK mutations, we will also offer specialized diagnostic testing for all newly diagnosed patients with neuroblastoma, to eventually allow oncologists to better customize treatment to a child’s genetic profile,” added Mossé.
In the next stage of the study, Mossé and colleagues looked at the more common form of neuroblastoma, the sporadic or non-inherited form. And again they found ALK mutations played an important role: they occurred in 12 per cent of 194 tumor samples of the aggressive, high-risk form of the disease.
The study is actually the first to report an example of a childhood cancer caused by mutations in a cancer-causing gene.
Scientists already knew that abnormalities in ALK were linked to lymphoma and lung cancer, where it triggers the translocation of DNA between chromosomes to make new cancer-causing genes. In this study, it appears that ALK gene mutations also trigger the production of neuroblastoma cells. This abnormality is an obvious target for treatments that inhibit the ALK protein that delivers the trigger.
Several drug companies are already developing ALK inhibitors, and one is going through early phase adult clinical trials for treating lung cancer and lymphoma.
Mossé and colleagues are planning pediatric clinical trials of ALK inhibitors in children with high-risk neuroblastoma.
“Identification of ALK as a major familial neuroblastoma predisposition gene.”
Yaël P. Mossé, Marci Laudenslager, Luca Longo, Kristina A. Cole, Andrew Wood, Edward F. Attiyeh, Michael J. Laquaglia, Rachel Sennett, Jill E. Lynch, Patrizia Perri, Geneviève Laureys, Frank Speleman, Cecilia Kim, Cuiping Hou, Hakon Hakonarson, Ali Torkamani, Nicholas J. Schork, Garrett M. Brodeur, Gian P. Tonini, Eric Rappaport, Marcella Devoto & John M. Maris.
Nature, Advance online publication, 24 August 2008.
DOI:10.1038/nature07261
Sources: Journal Abstract, Children’s Hospital of Philadelphia, ACS.
Written by: Catharine Paddock, PhD