Scientists Discover Neuroblastoma Gene

Ali Torkamani, PhD


October 06, 2008

Scientists have discovered that mutations in a gene called anaplastic lymphoma kinase (ALK) are a major cause of neuroblastoma in both inherited and noninherited forms of neuroblastoma.[1] Previous to this finding, it was known that numerous chromosomal abnormalities, including deletions of chromosome arms 1p, 11q, and 14q,[2,3] were associated with neuroblastoma, though no specific drug targets had been identified. Neuroblastoma is currently treated by surgery, chemotherapy, and/or radiation therapy[4] and is associated with a low (40%) survival probability[5] and 69% 5-year survival rate.[6] The discovery of ALK mutations in neuroblastoma provides an exciting opportunity to develop new approaches for therapy, and an ALK inhibitor has been tested for efficacy in non-small-cell lung cancer.[7]

Neuroblastoma accounts for 15% of childhood cancer mortality.[8] It is the most common form of cancer in infants.[9] Sixty percent of cases arise in children younger than 2 years and 97% before age 10 years.[8] According to the American Cancer Society, 650 new cases of neuroblastoma are diagnosed in the United States each year, 90% of which are diagnosed by age 5.[10] Neuroblastoma accounts for 6.7% of childhood cancers, behind brain/other nervous system and leukemia.[6] Neuroblastoma is a neuroendocrine tumor arising from neural crest cells that ultimately make up the sympathetic nervous system and most commonly begins in the adrenal gland, though it may also begin in the abdomen, thorax, neck, pelvis, and other sites.[9] Fifty to sixty percent of cases have metastases at diagnosis. The cause of neuroblastoma is largely unknown. Proposed risk factors for neuroblastoma include numerous parental factors such as smoking, alcohol consumption, and use of fertility drugs, diuretics, and hair-coloring products,[11,12] though epidemiologic studies have had inconsistent results. In a small percentage of cases, there is a familial history of the tumor.[13]

Yael Mossé and John Maris, in collaboration with an international team of investigators, first focused their efforts upon the rare group of neuroblastoma cases for which there was evidence of a heritable risk factor.[1] By performing a genome-wide linkage scan, a technique used to track large chromosomal pieces through family pedigrees in order to identify chromosomal pieces which follow incidences of the disease through the pedigree, a region on chromosome 2p that segregated with neuroblastoma in multiple families was identified. This region harbored 104 genes, including MYCN,[1] a gene that is commonly amplified in neuroblastoma tumors.[14] The MYCN gene and surrounding DNA was sequenced in probands of each family, and no disease-causal mutations were identified.[1]

Next, the group focused on the ALK gene. ALK is a tyrosine kinase, one of a family of proteins that add phosphate groups to other proteins. These phosphate groups act as switches that regulate the activity of other proteins. Thus, the phosphotransferase activity of tyrosine kinases is strictly controlled in normal cells. Mutations that abnormally activate the phosphotransferase activity of tyrosine kinases are a major cause of cancer in numerous tumor types. ALK, like MYCN, can be amplified in neuroblastoma.[15] In addition, chromosomal abnormalities that fuse the ALK gene to other genes occur in anaplastic large cell lymphoma,[16] inflammatory myofibroblastic tumors,[17] squamous cell carcinomas,[18] and non-small-cell lung cancers.[19] Therefore, the ALK gene provided a promising candidate oncogene in the 2p region. Sequencing of the ALK gene in probands of each family identified mutations that segregated with the disease.[1] These mutations were predicted to increase ALK activity by bioinformatic and structural analyses.

With a strong candidate gene involved in inherited neuroblastoma identified, the group next set out to determine whether mutations in ALK are involved in sporadic neuroblastoma cases. Sequencing of the ALK gene in sporadic neuroblastoma tumors and cell lines revealed ALK mutations in 8.4% of sporadic neuroblastoma cases and 35.7% of neuroblastoma cell lines.[1] These mutations were predicted to be activating, and a subset of these mutants was confirmed to be activating by the existence of phosphorylation marks on the ALK protein itself (autophosphorylation), the first step required for turning on ALK phosphotransferase activity. These autophosphorylation marks were absent in most nonmutant ALK neuroblastoma samples, though the presence of autophosphorylation marks in a few nonmutant ALK samples suggests multiple mechanisms for ALK activation.

The existence of ALK mutations in a large number of inherited and sporadic neuroblastoma cases provides an exciting opportunity for targeted pharmaceutical intervention in neuroblastoma. Therapies targeting tyrosine kinases, such as trastuzumab, which targets human epidermal growth factor receptor 2 tyrosine kinase in breast cancer, and gefitinib, which targets epidermal growth factor receptor tyrosine kinase in non-small-cell lung cancer, have proven to be immensely powerful treatment strategies.[20,21] Mossé and colleagues[1] reduced the levels of ALK in neuroblastoma samples carrying ALK mutations and found that ALK reduction significantly retarded tumor growth. In neuroblastoma samples without ALK mutations, tumor growth was retarded only in samples found to have autophosphorylation marks. This important observation suggests that a large portion of neuroblastoma tumors will be responsive to therapies targeting the ALK gene. Thus, not only does this discovery allow for genetic screening in families with a history of neuroblastoma, it also provides an Achilles' heel for this lethal childhood cancer for which treatment strategies were previously limited.


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