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Grant Details

Grant Number: 5R01CA098193-03 Interpret this number
Primary Investigator: Howe, James
Organization: University Of Iowa
Project Title: The Molecular Basis of Juvenile Polyposis
Fiscal Year: 2005
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Abstract

DESCRIPTION (provided by applicant): Juvenile Polyposis (JP) is a hamartomatous gastrointestinal polyposis syndrome in which affected patients are at significant risk for developing colorectal cancer. We have previously shown that JP is caused by germline mutations of SMAD4 and BMPR1A, implicating the bone morphogenetic and TGF-beta superfamily signaling pathways in JP-associated tumorigenesis. Microscopically, juvenile polyps have a markedly expanded lamina propria, with abundant stroma, an inflammatory infiltrate, and normal overlying epithelium. However, Jp-associated cancers are epithelial, and the process by which these polyps develop and how they transform to adenocarcinoma represents a unique and largely unexplored mechanism of carcinogenesis. The long-term goal of these studies is to define how cancers arise from juvenile polyps of the gastrointestinal tract. The objective of this application is to determine the molecular genetic events involved in juvenile polyp formation. The central hypothesis is that germline mutations in TGF-beta superfamily genes predispose patients to JP, and gastrointestinal polyps develop as a consequence of further alterations in these and related signaling pathways. We propose to achieve our objective through two Specific Aims: 1) To discover new JP genes by genetic linkage and positional candidate approaches; and 2) To examine patterns of global gene expression in the transcriptomes of juvenile polyps in order to define the common genetic pathways involved in their formation, and the specific contributions of different cell types within polyps to these expression patterns. Collectively, these studies will define the molecular genetic changes occurring in JP patients, beginning at birth with germline mutations and progressing through somatic alterations in the gastrointestinal tract, leading to juvenile polyps. Identification of a new JP gene will further define the specific TGF-beta superfamily pathways whose altered signaling brings about this phenotype, and gene expression studies will delineate the secondary events leading to juvenile polyps, and those genes whose transcription is affected by the germline mutations. The insights gained from this project will lay the groundwork for future studies to determine the specific genetic events required for the transformation of juvenile polyps into cancers, and to study the contribution of this novel mechanism of carcinogenesis in sporadic colorectal tumors. These studies will also benefit JP patients by improving presymptomatic genetic testing, and identification of new therapeutic targets for polyp regression and cancer prevention in JP.

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Publications

SP1 regulates the transcription of BMPR1A.
Authors: Dahdaleh F.S. , Carr J.C. , Calva D. , Howe J.R. , Howe J.R. .
Source: The Journal of surgical research, 2011 Nov; 171(1), p. e15-20.
EPub date: 2011-07-23.
PMID: 21872883
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Discovery of SMAD4 promoters, transcription factor binding sites and deletions in juvenile polyposis patients.
Authors: Calva D. , Dahdaleh F.S. , Woodfield G. , Weigel R.J. , Carr J.C. , Chinnathambi S. , Howe J.R. .
Source: Nucleic acids research, 2011 Jul; 39(13), p. 5369-78.
EPub date: 2011-03-17.
PMID: 21421563
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The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis.
Authors: Calva-Cerqueira D. , Chinnathambi S. , Pechman B. , Bair J. , Larsen-Haidle J. , Howe J.R. .
Source: Clinical genetics, 2009 Jan; 75(1), p. 79-85.
EPub date: 2008-09-24.
PMID: 18823382
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Hamartomatous polyposis syndromes.
Authors: Calva D. , Howe J.R. .
Source: The Surgical clinics of North America, 2008 Aug; 88(4), p. 779-817, vii.
PMID: 18672141
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Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells.
Authors: Mudhasani R. , Zhu Z. , Hutvagner G. , Eischen C.M. , Lyle S. , Hall L.L. , Lawrence J.B. , Imbalzano A.N. , Jones S.N. .
Source: The Journal of cell biology, 2008-06-30; 181(7), p. 1055-63.
PMID: 18591425
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A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis.
Authors: Howe J.R. , Chinnathambi S. , Calva D. , Bair J. , Pechman B. , Salamon A. , Tam B. , Simon L. .
Source: Cancer genetics and cytogenetics, 2008 Feb; 181(1), p. 52-4.
PMID: 18262054
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ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis.
Authors: Howe J.R. , Haidle J.L. , Lal G. , Bair J. , Song C. , Pechman B. , Chinnathambi S. , Lynch H.T. .
Source: Clinical genetics, 2007 Jan; 71(1), p. 91-2.
PMID: 17204053
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Hereditary colon cancer--part I.
Authors: Merg A. , Lynch H.T. , Lynch J.F. , Howe J.R. .
Source: Current problems in surgery, 2005 Apr; 42(4), p. 195-256.
PMID: 15821699
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