Fifteen years of genetic sleuthing has finally paid off: Researchers have nailed the gene that appears to cause an inherited form of neuroblastoma, a cancer of the nervous system that predominantly strikes children. Scientists are optimistic that the findings will allow them to develop disease screening for some families, as well as lead to potential new therapies.
About 15 years ago, a family riddled with neuroblastoma arrived at the Children's Hospital of Philadelphia (CHOP); even a grandmother had developed the disease. Pediatric oncologist John Maris realized that he had a rare clue on his hands. Just 700 children in North America are diagnosed with neuroblastoma, and only 1% of those have the familial form, passed down through other family members. Maris asked for permission to draw blood for DNA testing and was invited to a barbecue with the family; he arrived armed with needles and collected blood samples at the kitchen table. Over time, Maris and his colleague Yael Mossé reached out to hospital centers in Belgium, Italy, and elsewhere searching for more families like this one. Eventually, they found 20--a total of 49 people with neuroblastoma and 127 without.
Searching for shared DNA, the researchers quickly homed in on a region of chromosome 2. That led them to mutations in a gene called ALK, which, when activated, can promote cancer. The defective form of ALK, a dominant allele, appeared in all the affected individuals, as well as in healthy parents, who had passed it down, the team reports online this week in Nature. They also found ALK in some siblings who were healthy, making them wonder whether these youngsters were at high risk of neuroblastoma. ALK has also been implicated in lung cancer and lymphomas, although the molecular defects there are different.
The families studied here, who carry the ALK mutation, make up a tiny minority of those affected by neuroblastoma, however. Most children are the only ones in their family with the disease, developing it spontaneously for no apparent reason. Could the discovery of ALK in familial neuroblastoma help children who didn't inherit the gene?
To find out, the researchers studied tumor samples from children with neuroblastoma who hadn't inherited the disease. They found that 12% had ALK mutations in their tumors. What's more, a handful of children without a family history of the mutation carried ALK mutations in every cell in their body, meaning that they developed a spontaneous mutation in utero before going on to develop neuroblastoma. Together, these pieces suggested that ALK had a role to play in spontaneous neuroblastoma as well as the familial form, even if oncologists are still trying to sort out exactly what it might be.
Meanwhile, CHOP is gearing up to offer ALK testing to all newly diagnosed neuroblastoma patients. This will help physicians determine how common ALK mutations are in neuroblastoma tumors and help them identify children who may have developed mutations before they were born. For those who are ALK carriers--harboring the gene in their normal cells, as well as cancerous ones--CHOP will offer testing to healthy siblings, under the rationale that if these children also test positive, they can be given regular, noninvasive screening to catch the disease in its early stages. Mossé believes that this is critical, because by her estimate, the chance of developing neuroblastoma if one carries an ALK mutation is at least 50%. Most children with neuroblastoma are diagnosed once the disease has already spread and have a survival rate of about 30%.
"We're fortunate to not only have found this gene but to be able to do something about it," says Mossé. She's particularly grateful that the culprit is a gene that is activated to cause cancer--as opposed to one that's silenced and then triggers the disease--because drugs can suppress it. One ALK inhibitor is in a phase I trial for lung cancer, and the company, Pfizer, is willing to test it in neuroblastoma. Mossé expects a trial to open in 6 months.
"It's clear that these mutations are real," says pediatric oncologist Susan Cohn of the University of Chicago Comer Children's Hospital. "It's incredibly exciting." One thing that's unknown, she says, is whether ALK-inhibiting drugs will work on all types of neuroblastoma tumors, because not all tumors carry them. That's something only clinical trials will tell, she says.