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Mature Sex Dana

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Studies of inherited cancer syndromes have provided unique opportunities to uncover and explain important cellular pathways. Pleuropulmonary blastoma (PPB) is a rare lung sarcoma that arises during fetal lung development and affects children under 6 years of age. In approximately 20% of cases, PPB appears to develop as the result of inherited cancer susceptibility. We have recently demonstrated germline loss of function DICER1 mutations in familial PPB. We hypothesize that inactivation of the wild-type DICER1 allele leads to tumor formation through dysregulation of genes controlled by miRNAs. Three highly integrated aims are proposed to further define the role DICER1 plays in PPB. In Aim 1, we will define the heritability of PPB and further characterize the PPB tumor predisposition syndrome by systematically collecting comprehensive personal medical histories from extended family members from 100 PPB families. In Aim 2 we will determine DICER1's role in PPB predisposition performing DICER1 mutation analysis in 100 PPB children. For each proband with a DICER1 mutation, we will test parents, siblings, grandparents and more distantly related members for the presence of family-specific mutations. We will explore candidate genes in cases lacking DICER1 mutations. These experiments will shed light on the genetic heterogeneity of PPB and will allow us to measure the penetrance and expressivity of DICER1 mutations. In Aim 3 we will determine DICER1's role in PPB initiation and evaluate potential mechanisms of oncogenesis. We will use immunohistochemistry to evaluate DICER1 expression in both tumor-associated epithelial and mesenchymal components and to guide subsequent somatic mutation studies of DICER1. Conceptually, this tumor may represent a naturally-occurring model of mesenchymal cell dysregulation. Preliminary data suggests that loss of DICER1 (and mature miRNAs) may occur primarily in the non-neoplastic epithelial component of the tumor leading to dysregulation of """"""""tumor promoting factor(s)"""""""" that stimulate proliferation of the mesenchyme and predisposes the mesenchyme to sarcomatous transformation. The investigation of dysregulation in the context of malignancy may add to our knowledge base of epithelial-mesenchymal interactions in normal and abnormal lung development. The work proposed in this application will help test and refine this hypothesis and build the foundation for future mechanistic studies. A better understanding of this syndrome is essential to the development of clinical criteria for identifying these families and for guiding their medical care. Intensified radiologic screening examinations could be directed toward at-risk family members, leading to earlier detection of PPB in its purely cystic stage when the disease is more readily cured. In addition, study of families that show predisposition to PPB represent a unique opportunity to learn about the cellular processes in the borderland between development and neoplasia and to study how tissue-specific loss of DICER1 (and the miRNAs it regulates) manifests in human disease. 041b061a72


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