Scientists have found the cause of an inherited form of a rare type of childhood cancer and how the cancer develops, representing a whole new mechanism.

The researchers at Washington University School of Medicine in St. Louis, the Children's National Medical Center in Washington, D.C., the International Pleuropulmonary Blastoma Registry at Children's Hospitals and Clinics of Minnesota and other collaborating institutions, found that children with a rare, aggressive form of lung cancer called pleuropulmonary blastoma, or PPB, are born with a mutation in DICER1, itself a master controller gene that helps regulate other genes.

They also found children with PPB have normal-looking cells in their lungs that appear to cause neighboring cells to turn cancerous.

The results were presented Monday at the American Association for Cancer Research 100th Annual Meeting 2009 in Denver, Colorado.

PPB is the first malignancy found to be directly associated with inherited DICER1 mutations, making the cancer an important model for understanding how mutations and loss of DICER1 function lead to cancer," says lead author D. Ashley Hill, M.D., chief of pathology at Children's National Medical Center.

"Additionally, we now believe that PPB tumors arise from an unusual mechanism in which cells carrying mutations induce nearby cells to become cancerous without becoming cancerous themselves. "The researchers found that all the children studied with PPB carried damaging mutations in one of their DICER1 genes, giving them one functional and one nonfunctional DICER1 gene in all their body's cells. The researchers indicate that PPB lung tumors probably originate when one or more cells in the lung acquire a harmful mutation in their functional copy of the DICER1 gene.

The researchers also found that PPB lung tumors appear to result from a novel cancer induction mechanism not previously demonstrated. They discovered that loss of DICER1 protein specifically in lung airway cells appears to deregulate signals to nearby cells in which DICER1 itself still functions and somehow causes those cells to transform into malignant cells. However, the cells with the loss of DICER1 do not progress to malignancy.

PPB is so rare that it is only diagnosed in 10 to 20 children every year in the United States and 50 to 60 globally. Identified and treated early, it has a 90 percent cure rate but doctors rarely expect to find lung cancer in newborns or young children.

If not treated correctly, children only have about a 40 percent chance of survival.

The researchers analyzed DNA samples from 49 people in four families. About 40 percent of cases of PPB are found in children whose families have a history of some kind of cancer, suggesting an inherited genetic cause.

They were surprised to find the mutation in DICER1, which is named for its function chopping up large molecules into smaller molecules called microRNAs that help regulate other genes.

The people with the DICER1 mutations had the defect in every cell of the body, but the researchers found something else unusual. Seemingly normal lung cells, which carried an even more severe form of the mutation, were apparently causing neighboring cells to go haywire and form tumors.

"The cell, because it is screwed up, is inducing cancer in neighboring cells. That has never been seen before," said the researchers.

The researchers said finding this variant form of a gene in some PPB families is a first step to understanding why PPB and other conditions may occur in some families. But, because only a small number of families were studied it isn't known whether DICER1 mutations explain all PPB cases, and much more needs to be learned before this information can be directly helpful to PPB families.

(Agencies via Xinhua April 21, 2009)