For more than a decade, parents of children with neuroblastoma have been asking Dr. John Maris what causes the cancer, and until now he has had no answer. But new research led by his team at the Children's Hospital of Philadelphia (CHOP) is starting to provide clues that could lead to a genetic test and a clinical trial as early as next year.

The researchers have identified germline mutations in the anaplastic lymphoma kinase (ALK) gene in the vast majority of families with the inherited form of the disease. The discovery has generated interest in the field because ALK is a known cancer gene (oncogene) and drugs against this target are in development. The ALK protein - a receptor tyrosine kinase - helps regulate cell growth and may be abnormally activated in cancer.

"This is an incredibly exciting discovery," said Dr. Susan Cohn, an expert on neuroblastoma at the University of Chicago, who was not involved in the study. "If we're lucky, the discovery will dramatically impact the way we approach patients with neuroblastoma in the future."

While familial cases of neuroblastoma account for only 1 percent of all cases, ALK mutations can also occur as tumors grow and spread in the more common non-hereditary forms. The researchers found ALK mutations in 12 percent of high-risk neuroblastoma tumor samples, and the gene is amplified (present in multiple copies) in up to an additional 5 percent of tumors.

Neuroblastoma arises in children in the developing cells of the sympathetic nervous system, and it often appears as a tumor in the chest or abdomen. Half of children with the disease have the high-risk form, which has long-term survival rates of only 40 percent at best and often resists standard therapies.

Reporting their findings online in Nature last month, the researchers concluded that ALK mutations appear to drive the disease in a subset of neuroblastoma patients. Even before the initial findings were presented at a scientific meeting last spring, other laboratories had implicated ALK mutations in the disease.

By early 2009, the researchers expect to have a genetic test available. The test could identify family members of patients with neuroblastoma who harbor ALK mutations. These individuals could be carefully monitored using noninvasive techniques such as ultrasound or a urine test. If the ALK protein turns out to be an important therapeutic target, testing could be applied broadly to guide treatment.

Dr. Maris and his coauthor, Dr. Yael P. Mossé, also at CHOP, are in discussions with a pharmaceutical company about opening a trial of an ALK inhibitor for children with neuroblastoma next year.

The ALK gene was discovered in 1994 in patients with a large-cell lymphoma. It has since been shown to play a role in multiple cancers, including lung and esophageal. In these diseases, ALK merges with other genes in "translocations" that drive cell growth by activating the ALK kinase.

To demonstrate a role for ALK in inherited neuroblastoma, the researchers scanned the DNA of 10 families with two or more affected members. Three inherited mutations in ALK tracked with the disease in eight separate families.

The researchers then analyzed nearly 200 high-risk neuroblastoma samples and found spontaneous, or non-inherited, mutations in 12 percent. An effort to characterize the full spectrum of ALK mutations and when the mutations occur is underway.

"There appear to be some mutations where all individuals who carry them will manifest the disease and other mutations that are less likely to cause the disease," said Dr. Mossé. It may be that a second genetic "hit," such as the amplification of ALK, is required to cause the disease in most patients, she noted.

An interesting finding of the study was that experimentally inhibiting ALK signaling reduced the proliferation of neuroblastoma cells, even in cells with no known ALK mutations. This suggests that targeting ALK may benefit patients with normal ALK genes, but the researchers caution that clinical trials are needed to answer these questions. This is likely to happen soon.

"Translating this discovery from the Maris laboratory into the clinic will be a high priority for neuroblastoma researchers," said Dr. Malcolm Smith of NCI's Cancer Therapy Evaluation Program.

Dr. Smith, along with Dr. Maris, leads the Neuroblastoma TARGET Initiative, which uses genomic strategies to identify and validate therapeutic targets for the disease. The group is already sequencing the ALK gene in additional neuroblastoma cases and other genes as well.

In a genome-wide association study published last May, Dr. Maris' group identified a region of chromosome 6 that may contain genetic variants associated with aggressive neuroblastoma. This study and the current one were completely separate, but each produced novel insights into the genetics of neuroblastoma, noted Dr. Maris.

"We know a whole lot more about what causes the disease today than we did a year ago," he said.

—Edward R. Winstead