Identifying the Genetic Basis of the Pleuropulmonary Blastoma (PPB) Family Cancer Syndrome
Christina Gurnett, M.D., Ph.D.
Ashley Hill, M.D.
Pathology and Immunology
Center for Pediatric Pulmonary Disease
Interdisciplinary Research Initiative
2/1/2007 - 7/31/2009
Brian Suarez, Paul Goodfellow, Mark Watson, Alison Whelan
Pleuropulmonary blastoma (PPB) is a rare malignant lung tumor that arises during fetal development. Most cases are diagnosed in children less than five years of age. Nearly half of children with PPB die. While the clinical and pathologic aspects of PPB have been well characterized, the molecular basis of PPB is not known. Several lines of evidence suggest a strong genetic component including 1) early onset of disease, 2) synchronous or metachronous tumors in the lung or other organs, and 3) the excess of a unique constellation of rare, primarily pediatric, tumor types in first and second degree relatives. The increased incidence of other developmentally related neoplasms in PPB patients and their family members is remarkable and suggests that these tumors may share a common pathogenesis. Dr. Hill is testing the genetic basis for the PPB Family Cancer syndrome by fully characterizing the clinical features of the PPB Syndrome and mapping the PPB Syndrome susceptibility locus(loci).
Our funded study of 12 families with pleuropulmonary blastoma culminated last year with the discovery of the gene responsible for this rare, aggressive childhood lung tumor. The gene responsible, DICER1, is a master controller that helps regulate the expression of other genes, through its processing of microRNAs.
The results provide these families with the possibility of improved diagnosis and prevention. these results have larger implications for the understanding and treatment of many types of cancer. Discovery of the role of DICER 1 may one day allow us to o prevent serious disease by improved screening of family members with the genetic risk factor. From a therapeutic standpoint, DICER1 may represent a specific drug target for patients with cancer. Furthermore, the role of DICER and genes in this developmental pathway may play a larger role in other pediatric tumors and warrants further study.
As a result of our Institute funded research, we published a paper in the journal Science, thus disseminating our findings to the wider scientific community.1 In June 2009, we received $1.25 million in funding from the National Institutes of Health to study DICER 1 in pediatric tumors.
Note: 1. 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, Messenger Y, Goodfellow PJ. DICER1 mutations in familial pleuropulmonary blastoma, Science. 2009, 325(5943):965.