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Genetic Source of Rare Childhood Cancer Found; Gene is Implicated in Other Cancers

DENVER, April 19 /PRNewswire/ -- The search for the cause of an inherited form of a rare, aggressive childhood lung cancer has uncovered important information about how the cancer develops and potentially sheds light on the development of other cancers.

The finding by 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 adds the final link to the chain connecting the gene DICER1 to cancer development -- something that had been suspected but until now not definitively demonstrated.

The results were presented today at the American Association for Cancer Research 100th Annual Meeting 2009 in Denver, Colorado. The study shows that some children with the rare cancer pleuropulmonary blastoma (PPB) are born with a deleterious mutation in DICER1, a master controller gene that helps regulate expression of other genes. The children studied came from families with a history of PPB or related disorders.

"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."

Hill was principal investigator of the study, which was begun while she was on the Washington University faculty.

Only 50 to 60 cases of PPB are diagnosed each year around the world. Most children with PPB are under five years of age. The cancer progresses from air-filled lung cysts in the early stage to solid lung tumors in later stages. If detected in the earliest stage, 90 percent of patients appear to be cured when treated with surgery and sometimes chemotherapy. Overall survival drops to about 40 percent if the cancer is diagnosed in the latest stage.

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.

DICER1 is so-named because its job is to chop up large molecules into smaller control molecules that help regulate the output of many of the 30,000 human genes. The short bits of genetic material it produces during its dicing activities are termed microRNAs.

"Prior research showed that the microRNA profiles of cancer cells are different from those of normal tissue, which pointed toward a possible role for DICER1 in cancer," says senior author Paul Goodfellow, Ph.D., co-director of the Hereditary Cancer Core at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "Very recently, other research found that reduced DICER1 gene expression in tumor cells is associated with worse outcomes in patients with ovarian, lung, breast and prostate cancers. Now we've shown that mutations in the DICER1 gene are directly linked to the development of PPB."

"For years our large collection of cases of PPB and families has revealed the strong genetic component of this disease," said Jack Priest, M.D., research director of the International PPB Registry in Minnesota. "We are thrilled that our colleagues Drs. Hill and Goodfellow uncovered an important mutation and have begun to understand the cellular mix-up which results in malignancy." Current studies show around 40 percent of PPB cases occur in families with a history of the disease or certain other childhood cancers. In contrast, most pediatric cancers occur sporadically, without any familial patterns. This led scientists and doctors to suspect that the cancers were caused by an inherited genetic abnormality. To uncover the role of DICER1, the research team studied the genetic makeup of 11 extended families with two or more members having PPB or related childhood cancers.

The scientists say that 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.

In collaboration with Drs. Hill and Goodfellow, and with Louis P Dehner, M.D., of Washington University St. Louis, who first described PPB in 1988, the International PPB Registry in Minnesota has collected and analyzed PPB cases from around the world for more than 20 years. More than 260 confirmed cases are being followed. The Registry is funded by Minneapolis/St. Paul-area foundations and is the only organization in the world focused exclusively on PPB.

Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. Germline DICER1 mutations in familial pleuropulmonary blastoma.

Funding from the Siteman Cancer Center, Children's Discovery Institute at St. Louis Children's Hospital and Washington University School of Medicine, Hope Street Kids Foundation, Foundation of Children's Hospitals and Clinics of Minnesota - Pine Tree Apple Tennis Classic, Washington University Department of Pathology, St. Louis Children's Hospital Foundation and the Urological Research Foundation supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.

Children's National Medical Center, located in Washington, DC, is a proven leader in the development of innovative new treatments for childhood illness and injury. Children's has been serving the nation's children for more than 135 years. Children's National is proudly ranked among the best pediatric hospitals in America by US News & World Report and the Leapfrog Group. For more information, visit Children's Research Institute, the academic arm of Children's National Medical Center, encompasses the translational, clinical, and community research efforts of the institution. Learn more about our research programs at

Serving as Minnesota's children's hospital since 1924, Children's Hospitals and Clinics of Minnesota is the seventh-largest pediatric health care organization in the United States, with 332 staffed beds at its two hospitals in St. Paul and Minneapolis. An independent, not-for-profit health care system, Children's of Minnesota provides care through more than 14,000 inpatient visits and more than 200,000 emergency room and other outpatient visits every year. Children's is the only Minnesota hospital system to provide comprehensive care exclusively to children, and in 2008 was ranked among the best pediatric hospitals by U.S. News & World Report.

SOURCE Children's Hospitals and Clinics of Minnesota; Washington University School of Medicine in St. Louis; Children's National Medical Center in Washington, D.C.
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