[1710] DICER1 Mutations in Familial PPB-Tumor Predisposition Syndrome-Associated and Sporadic Rhabdomyosarcomas.

Jason A Jarzembowski, Leslie Doros, D Ashley Hill, Jiandong Yang, Kerry Skiver, Yoav H Messinger, Gretchen Williams, Louis P Dehner. Children's Hospital of Wisconsin, Milwaukee; Children's National Medical Center, Washington, DC; The International Pleuropulmonary Blastoma Registry, Minneapolis, MN; Washington University in St. Louis, MO

Background: Pleuropulmonary blastoma (PPB), a rare dysontogenic tumor of the lung, appears to arise as a perturbation in the branching morphogenetic phase of lung development with the added capacity for malignant progression. This initial multicystic lesion is accompanied by a primitive population of cells with or without an embryonal rhabdomyosarcoma [ERMS]-like component. We recently discovered that patients with a familial PPB-tumor predisposition have germline loss-of-function mutations in DICER1, an miRNA processing enzyme which helps orchestrate organogenesis. We have also observed that some ERMS, especially those of the uterine cervix, resemble PPB with cartilaginous nodules and septated cysts. Because of the histologic overlap between PPB and ERMS and their co-occurrence in some syndromic families we investigated the role of DICER1 in ERMS.
Design: Three probands and one uncle from PPB syndromic families were diagnosed with extrathoracic RMS (1 uterine cervix, 3 bladder). Germline DNA from these cases along with tumor DNA from an additional 52 ERMS obtained from the Cooperative Human Tissue Network (CHTN) archive were analyzed for DICER1 mutations by directly sequencing all coding exons and flanking sequences.
Results: All 4 ERMS in PPB families had loss of function DICER1 mutations: 2 were nonsense mutations and 2 were insertion/deletion variants. Of the 52 ERMS without PPB syndrome, 2 had DICER1 mutations: 1 insertion/deletion and 1 splice junction mutation. All 6 mutations are predicted to result in loss of functional DICER1 from this allele.
Conclusions: Our findings suggest that a small but significant fraction (4%) of pediatric ERMS harbor DICER1 mutations, suggesting a role for miRNAs in the pathogenesis of these tumors. Germline DNA from most cases was not available, and we cannot determine whether the mutations are tumor-specific or germline. Inherited germline mutations are found in the majority of children with PPB, most of whom show no other signs of the familial PPB-tumor syndrome. It will be important to know if patients with "sporadic" ERMS have germline mutations because then they, their progeny, and their family members are potentially at risk for developing PPB and other malignancies and should be counseled.
Category: Pediatrics

Monday, February 28, 2011 11:00 AM

Platform Session: Section H 2, Monday Morning


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