signs of hope. Identification of a gene behind neuroblastoma may help in screening and therapies
Sonya N. Herbert / Corbis News
Fifteen years of genetic sleuthing finally paid .: researchers have nailed the gene that seems to cause an inherited form of neuroblastoma, a cancer of the nervous system that primarily affects children. Scientists are optimistic that the results will help them develop disease screening for some families, and lead to potential new therapies.
thereabout 15 years, a family riddled with neuroblastoma arrived at the Philadelphia Children's Hospital (CHOP); even a grandmother had developed the disease. Pediatric oncologist John Maris realized that he had a rare clue to his hands. Only 700 children in North America are diagnosed with neuroblastoma, and only 1% of those with familial, transmitted through other family members. Maris asked permission to draw blood for DNA tests and was invited to a barbecue with the family; he came armed with needles and collected blood samples at the kitchen table. Over time, Maris and his colleague Yael Mosse reached to hospitals in Belgium, Italy and elsewhere to look for other families like this. Finally, they found 20 to 1 total of 49 people with neuroblastoma and 127 without
In search of the shared DNA, the researchers quickly hosted on a region of chromosome 2. This 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 concerned, as well as in healthy parents, who had passed down, reports Team online this week in Nature . They also found ALK some brothers and sisters who were healthy, making them wonder if these young people were high-risk neuroblastoma. ALK has also been implicated in lung cancer and lymphoma, although there are different molecular defects.
The families studied here who wear ALK mutation, make up a small minority of those affected by neuroblastoma, however. Most children are the only ones in their family with the disease, develop spontaneously for no apparent reason. Could the discovery of ALK family in neuroblastoma help children who inherit the gene?
To find out, researchers studied tumor samples from children with neuroblastoma who did not inherit the disease. They found that 12% had ALK mutations in their tumors. In addition, a handful of children with no family history of the mutation carried ALK mutations in all cells of the body, which means they have developed a spontaneous mutation in utero before continuing to develop neuroblastoma. Together, these pieces suggested ALK had a role in neuroblastoma spontaneous and familial, although oncologists are still trying to unravel exactly what it might be.
Meanwhile, CHOP is preparing to offer ALK tests for all patients newly diagnosed neuroblastoma. This will help doctors determine how common ALK mutations in neuroblastoma tumors and help to identify children who may have developed mutations before birth. For those who are ALK carriers - harboring the gene in their normal cells as well as cancerous - CHOP offer tests for the brothers and healthy sisters, in the sense that if these children are also testing positive, they can be given regular, non-invasive screening to catch the disease in its early stages. Mosse considers it essential, because by his estimation, the risk of developing neuroblastoma when wearing a ALK mutation is at least 50%. Most children with neuroblastoma are diagnosed when the disease has already spread and has a rate of approximately 30% survival.
"We have the chance not only to have found this gene, but to be able to do something about it," said Mosse. She is particularly grateful that the culprit is a gene that is activated to cause cancer - as opposed to one that is silenced, then triggers the disease - because the drugs can suppress. One ALK inhibitor is in a Phase I trial for lung cancer, and the company, Pfizer, is ready to test it in neuroblastoma. Mosse awaiting trial to open in 6 months.
"It is clear that these changes are real," said pediatric oncologist Susan Cohn of the University of Chicago Comer Children's Hospital. "It is incredibly exciting." One thing that is unknown, she said, is whether ALK inhibiting drugs work on all types of neuroblastoma tumors, because all tumors carry them. This is something that only clinical trials will tell, she said.
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