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Grant Details

Grant Number: 5R01CA143167-03 Interpret this number
Primary Investigator: Hill, Dana
Organization: Children'S Research Institute
Project Title: Dicer1 and the Pleuropulmonary Blastoma Family Cancer Syndrome
Fiscal Year: 2012
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DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This work will shed light on the role genetics plays in a new pediatric tumor syndrome and could ultimately lead to new strategies to the detection and treatment of PPB and related tumors such as rhabdomyosarcoma and Wilms tumor.

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DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry.
Authors: Schultz K.A.P. , Harris A.K. , Finch M. , Dehner L.P. , Brown J.B. , Gershenson D.M. , Young R.H. , Field A. , Yu W. , Turner J. , et al. .
Source: Gynecologic Oncology, 2017 Dec; 147(3), p. 521-527.
EPub date: 2017-10-14 00:00:00.0.
PMID: 29037807
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The prevalence of DICER1 pathogenic variation in population databases.
Authors: Kim J. , Field A. , Schultz K.A.P. , Hill D.A. , Stewart D.R. .
Source: International Journal Of Cancer, 2017-11-15 00:00:00.0; 141(10), p. 2030-2036.
EPub date: 2017-08-21 00:00:00.0.
PMID: 28748527
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Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study.
Authors: Khan N.E. , Bauer A.J. , Schultz K.A.P. , Doros L. , Decastro R.M. , Ling A. , Lodish M.B. , Harney L.A. , Kase R.G. , Carr A.G. , et al. .
Source: The Journal Of Clinical Endocrinology And Metabolism, 2017-05-01 00:00:00.0; 102(5), p. 1614-1622.
PMID: 28323992
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Pediatric Cystic Nephroma Is Morphologically, Immunohistochemically, And Genetically Distinct From Adult Cystic Nephroma
Authors: Li Y. , Pawel B.R. , Hill D.A. , Epstein J.I. , Argani P. .
Source: The American Journal Of Surgical Pathology, 2017-02-07 00:00:00.0; , .
PMID: 28177962
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Type I Pleuropulmonary Blastoma versus Congenital Pulmonary Airway Malformation Type IV.
Authors: Dehner L.P. , Messinger Y.H. , Williams G.M. , Stewart D.R. , Harney L.A. , Schultz K.A. , Hill D.A. .
Source: Neonatology, 2017; 111(1), p. 76.
EPub date: 2016-08-26 00:00:00.0.
PMID: 27562209
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Pulmonary and pleural pathology: Contributions of Dr. Louis "Pepper" Dehner.
Authors: Ritter J.H. , Hill D.A. .
Source: Seminars In Diagnostic Pathology, 2016 Nov; 33(6), p. 450-461.
EPub date: 2016-09-21 00:00:00.0.
PMID: 27838088
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Comment on: DICER1-Negative Pleuropulmonary Blastoma in a Patient With Selective IgA Deficiency.
Authors: Stewart D.R. , Givens S.S. , Harris A.K. , Williams G.M. , Messinger Y.H. , Schultz K.A. , Hill D.A. .
Source: Pediatric Blood & Cancer, 2016 Oct; 63(10), p. 1869-70.
PMID: 27238822
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Ovarian Sex Cord-stromal Tumors
Authors: Schultz K.A. , Harris A.K. , Schneider D.T. , Young R.H. , Brown J. , Gershenson D.M. , Dehner L.P. , Hill D.A. , Messinger Y.H. , Frazier A.L. .
Source: Journal Of Oncology Practice, 2016 Oct; 12(10), p. 940-946.
PMID: 27858560
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Pediatric cystic nephromas: distinctive features and frequent DICER1 mutations.
Authors: Cajaiba M.M. , Khanna G. , Smith E.A. , Gellert L. , Chi Y.Y. , Mullen E.A. , Hill D.A. , Geller J.I. , Dome J.S. , Perlman E.J. .
Source: Human Pathology, 2016 Feb; 48, p. 81-7.
PMID: 26772403
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Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry.
Authors: Schultz K.A. , Harris A. , Messinger Y. , Sencer S. , Baldinger S. , Dehner L.P. , Hill D.A. .
Source: Familial Cancer, 2016 Jan; 15(1), p. 105-10.
PMID: 26289771
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DICER1 Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association.
Authors: Rutter M.M. , Jha P. , Schultz K.A. , Sheil A. , Harris A.K. , Bauer A.J. , Field A.L. , Geller J. , Hill D.A. .
Source: The Journal Of Clinical Endocrinology And Metabolism, 2016 Jan; 101(1), p. 1-5.
PMID: 26555935
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Can congenital pulmonary airway malformation be distinguished from Type I pleuropulmonary blastoma based on clinical and radiological features?
Authors: Feinberg A. , Hall N.J. , Williams G.M. , Schultz K.A. , Miniati D. , Hill D.A. , Dehner L.P. , Messinger Y.H. , Langer J.C. .
Source: Journal Of Pediatric Surgery, 2016 Jan; 51(1), p. 33-7.
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Pleuropulmonary Blastoma: Evolution of an Entity as an Entry into a Familial Tumor Predisposition Syndrome.
Authors: Dehner L.P. , Messinger Y.H. , Schultz K.A. , Williams G.M. , Wikenheiser-Brokamp K. , Hill D.A. .
Source: Pediatric And Developmental Pathology : The Official Journal Of The Society For Pediatric Pathology And The Paediatric Pathology Society, 2015 Nov-Dec; 18(6), p. 504-11.
EPub date: 2015-12-23 00:00:00.0.
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Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry.
Authors: Messinger Y.H. , Stewart D.R. , Priest J.R. , Williams G.M. , Harris A.K. , Schultz K.A. , Yang J. , Doros L. , Rosenberg P.S. , Hill D.A. , et al. .
Source: Cancer, 2015-01-15 00:00:00.0; 121(2), p. 276-85.
EPub date: 2015-01-15 00:00:00.0.
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Reply: Serum microRNA screening for DICER1-associated pleuropulmonary blastoma.
Authors: Schultz K.A. , Harris A. , Williams G.M. , Baldinger S. , Doros L. , Valusek P. , Frazier A.L. , Dehner L.P. , Messinger Y. , Hill D.A. .
Source: Pediatric Blood & Cancer, 2014 Dec; 61(12), p. 2331-2.
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Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
Authors: Pugh T.J. , Yu W. , Yang J. , Field A.L. , Ambrogio L. , Carter S.L. , Cibulskis K. , Giannikopoulos P. , Kiezun A. , Kim J. , et al. .
Source: Oncogene, 2014-11-06 00:00:00.0; 33(45), p. 5295-302.
EPub date: 2014-11-06 00:00:00.0.
PMID: 24909177
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Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder.
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Source: Human Genetics, 2014 Nov; 133(11), p. 1443-50.
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DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.
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Judicious DICER1 testing and surveillance imaging facilitates early diagnosis and cure of pleuropulmonary blastoma.
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DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome.
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Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations.
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Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry.
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DICER1 mutations in familial pleuropulmonary blastoma.
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