Grant Number:	5R01CA123010-02 Interpret this number
Primary Investigator:	Young, Joanne
Organization:	Queensland Institute Of Medical Research
Project Title:	Genetics of Serrated Neoplasia
Fiscal Year:	2008

DESCRIPTION (provided by applicant): Recently, an alternative pathway of neoplastic development has been identified in the colorectum which differs from the traditional adenoma-carcinoma pathway in that it is (a) associated with "serrated" precursor lesions and (b) driven by hypermethylation of multiple gene promoters and activating mutations in the BRAF proto-oncogene. At least 10-15% of CRC is likely to develop on the basis of a strong genetic predisposition. The two most well-characterized syndromes FAR and HNPCC both develop via the adenoma-carcinoma pathway and together account for approximately one-third of familial CRC. We have recently described several families in which there is evidence that the genetic predisposition to autosomal dominant CRC has its origins in the serrated pathway. This condition, Serrated Pathway Syndrome (SPS), and the related condition, Hyperplastic Polyposis (HPP), represent two syndromes in which BRAF mutation and methylation co-occur within serrated precursor lesions. The primary aim of this proposal is to identify the gene or genes which predispose to SPS and HPP. We will achieve this by carrying out a linkage study and fine-mapping procedure of well-characterised families with serrated neoplasia from Australasia, USA and Canada, supplemented and extended by candidate gene analysis, and expression profiling of normal tissue. The potential key outcome of this proposal will be the definition of the underlying genetic predisposition to develop serrated neoplasia. Currently, such families are unable to be offered presymptomatic testing. Recognition of this syndrome will allow families to be more definitively monitored for the lesions that act as precursors to their CRC, thereby preventing potential deaths. Presymptomatic testing of germline DNA will target screening to those individuals most at risk for developing colorectal cancer. Knowledge gained from this project will lead to a greater understanding of the disease mechanism, the opportunity for prevention (both chemo-prevention and screening endoscopy) and the development of novel treatment modalities. LAY DESCRIPTION: Colorectal cancer was once believed to develop only from a certain kind of polyp in the colon called the adenoma. However, recently another type of polyp called the hyperplastic polyp was found to also be capable of producing a cancer. In this proposal, we will explore the notion that the predisposition to form hyperplastic polyps may be inherited in families.




Serrated polyposis: the problem of definition and its relationship to the population at risk for syndrome-related colorectal cancer.
Authors: Young J.P. , Price T.J. , Parry S. .
Source: Translational Cancer Research, 2017 Dec; 6(Suppl 9), p. S1480-S1483.
PMID: 31179234
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Multiplicity And Molecular Heterogeneity Of Colorectal Carcinomas In Individuals With Serrated Polyposis
Authors: Rosty C. , Walsh M.D. , Walters R.J. , Clendenning M. , Pearson S.A. , Jenkins M.A. , Win A.K. , Hopper J.L. , Sweet K. , Frankel W.L. , et al. .
Source: The American Journal Of Surgical Pathology, 2013 Mar; 37(3), p. 434-42.
PMID: 23211288
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Germline Mutations In The Polyposis-associated Genes Bmpr1a, Smad4, Pten, Mutyh And Grem1 Are Not Common In Individuals With Serrated Polyposis Syndrome
Authors: Clendenning M. , Young J.P. , Walsh M.D. , Woodall S. , Arnold J. , Jenkins M. , Win A.K. , Hopper J.L. , Sweet K. , Gallinger S. , et al. .
Source: Plos One, 2013; 8(6), p. e66705.
PMID: 23805267
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Phenotype And Polyp Landscape In Serrated Polyposis Syndrome: A Series Of 100 Patients From Genetics Clinics
Authors: Rosty C. , Buchanan D.D. , Walsh M.D. , Pearson S.A. , Pavluk E. , Walters R.J. , Clendenning M. , Spring K.J. , Jenkins M.A. , Win A.K. , et al. .
Source: The American Journal Of Surgical Pathology, 2012 Jun; 36(6), p. 876-82.
PMID: 22510757
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Cancer Risks For Relatives Of Patients With Serrated Polyposis
Authors: Win A.K. , Walters R.J. , Buchanan D.D. , Jenkins M.A. , Sweet K. , Frankel W.L. , de la Chapelle A. , McKeone D.M. , Walsh M.D. , Clendenning M. , et al. .
Source: The American Journal Of Gastroenterology, 2012 May; 107(5), p. 770-8.
PMID: 22525305
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Linkage To Chromosome 2q32.2-q33.3 In Familial Serrated Neoplasia (jass Syndrome)
Authors: Roberts A. , Nancarrow D. , Clendenning M. , Buchanan D.D. , Jenkins M.A. , Duggan D. , Taverna D. , McKeone D. , Walters R. , Walsh M.D. , et al. .
Source: Familial Cancer, 2011 Jun; 10(2), p. 245-54.
PMID: 21165777
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Serrated Polyposis: An Enigmatic Model Of Colorectal Cancer Predisposition
Authors: Rosty,C. , Parry,S. , Young,J.P. .
Source: Pathology Research International, 2011; 2011, p. 157073.
PMID: 21660283
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Risk Factors: Hyperplastic Polyposis Syndrome And Risk Of Colorectal Cancer
Authors: Young J.P. , Parry S. .
Source: Nature Reviews. Gastroenterology & Hepatology, 2010 Nov; 7(11), p. 594-5.
PMID: 21042338
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Risk Factors For Colorectal Cancer In Patients With Multiple Serrated Polyps: A Cross-sectional Case Series From Genetics Clinics
Authors: Buchanan D.D. , Sweet K. , Drini M. , Jenkins M.A. , Win A.K. , English D.R. , Walsh M.D. , Clendenning M. , McKeone D.M. , Walters R.J. , et al. .
Source: Plos One, 2010-07-16 00:00:00.0; 5(7), p. e11636.
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Phenotypic Diversity In Patients With Multiple Serrated Polyps: A Genetics Clinic Study
Authors: Buchanan D.D. , Sweet K. , Drini M. , Jenkins M.A. , Win A.K. , Gattas M. , Walsh M.D. , Clendenning M. , McKeone D. , Walters R. , et al. .
Source: International Journal Of Colorectal Disease, 2010 Jun; 25(6), p. 703-12.
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Lessons From Lynch Syndrome: A Tumor Biology-based Approach To Familial Colorectal Cancer
Authors: Buchanan D.D. , Roberts A. , Walsh M.D. , Parry S. , Young J.P. .
Source: Future Oncology (london, England), 2010 Apr; 6(4), p. 539-49.
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A Perspective On Bi-allelic Mutyh Mutations In Patients With Hyperplastic Polyposis Syndrome
Authors: Buchanan D. , Young J. .
Source: Gastroenterology, 2009 Jun; 136(7), p. 2407-8.
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Analysis Of Families With Lynch Syndrome Complicated By Advanced Serrated Neoplasia: The Importance Of Pathology Review And Pedigree Analysis
Authors: Walsh M.D. , Buchanan D.D. , Walters R. , Roberts A. , Arnold S. , McKeone D. , Clendenning M. , Ruszkiewicz A.R. , Jenkins M.A. , Hopper J.L. , et al. .
Source: Familial Cancer, 2009; 8(4), p. 313-23.
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