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Grant Details

Grant Number: 5R01CA123010-03 Interpret this number
Primary Investigator: Young, Joanne
Organization: Queensland Institute Of Medical Research
Project Title: Genetics of Serrated Neoplasia
Fiscal Year: 2009
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Abstract

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.

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Publications

Multiplicity and molecular heterogeneity of colorectal carcinomas in individuals with serrated polyposis.
Authors: Rosty C, Walsh MD, Walters RJ, Clendenning M, Pearson SA, Jenkins MA, Win AK, Hopper JL, Sweet K, Frankel WL, Aronson M, Gallinger S, Goldblatt J, Tucker K, Greening S, Gattas MR, Woodall S, Arnold J, Walker NI, Parry S, Young JP, Buchanan DD
Source: Am J Surg Pathol, 2013 Mar;37(3), p. 434-42.
PMID: 23211288
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Cancer risks for relatives of patients with serrated polyposis.
Authors: Win AK, Walters RJ, Buchanan DD, Jenkins MA, Sweet K, Frankel WL, de la Chapelle A, McKeone DM, Walsh MD, Clendenning M, Pearson SA, Pavluk E, Nagler B, Hopper JL, Gattas MR, Goldblatt J, George J, Suthers GK, Phillips KD, Woodall S, Arnold J, Tucker K, Field M, Greening S, Gallinger S, Aronson M, Perrier R, Woods MO, Green JS, Walker N, Rosty C, Parry S, Young JP
Source: Am J Gastroenterol, 2012 May;107(5), p. 770-8.
EPub date: 2012 Apr 24.
PMID: 22525305
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Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics.
Authors: Rosty C, Buchanan DD, Walsh MD, Pearson SA, Pavluk E, Walters RJ, Clendenning M, Spring KJ, Jenkins MA, Win AK, Hopper JL, Sweet K, Frankel WL, Aronson M, Gallinger S, Goldblatt J, Woodall S, Arnold J, Walker NI, Jass JR, Parry S, Young JP
Source: Am J Surg Pathol, 2012 Jun;36(6), p. 876-82.
PMID: 22510757
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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 DD, Jenkins MA, Duggan D, Taverna D, McKeone D, Walters R, Walsh MD, Young BW, Jass JR, Rosty C, Gattas M, Pelzer E, Hopper JL, Goldblatt J, George J, Suthers GK, Phillips K, Parry S, Woodall S, Arnold J, Tucker K, Muir A, Drini M, Macrae F, Newcomb P, Potter JD, Pavluk E, Lindblom A, Young JP
Source: Fam Cancer, 2011 Jun;10(2), p. 245-54.
PMID: 21165777
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Risk factors: Hyperplastic polyposis syndrome and risk of colorectal cancer.
Authors: Young JP, Parry S
Source: Nat Rev Gastroenterol Hepatol, 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 DD, Sweet K, Drini M, Jenkins MA, Win AK, English DR, Walsh MD, Clendenning M, McKeone DM, Walters RJ, Roberts A, Pearson SA, Pavluk E, Hopper JL, Gattas MR, Goldblatt J, George J, Suthers GK, Phillips KD, Woodall S, Arnold J, Tucker K, Muir A, Field M, Greening S, Gallinger S, Perrier R, Baron JA, Potter JD, Haile R, Frankel W, de la Chapelle A, Macrae F, Rosty C, Walker NI, Parry S, Young JP
Source: PLoS One, 2010 Jul 16;5(7), p. e11636.
EPub date: 2010 Jul 16.
PMID: 20661287
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Lessons from Lynch syndrome: a tumor biology-based approach to familial colorectal cancer.
Authors: Buchanan DD, Roberts A, Walsh MD, Parry S, Young JP
Source: Future Oncol, 2010 Apr;6(4), p. 539-49.
PMID: 20373868
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Phenotypic diversity in patients with multiple serrated polyps: a genetics clinic study.
Authors: Buchanan DD, Sweet K, Drini M, Jenkins MA, Win AK, Gattas M, Walsh MD, Clendenning M, McKeone D, Walters R, Roberts A, Young A, Hampel H, Hopper JL, Goldblatt J, George J, Suthers GK, Phillips K, Young GP, Chow E, Parry S, Woodall S, Tucker K, Muir A, Field M, Greening S, Gallinger S, Green J, Woods MO, Spaetgens R, de la Chapelle A, Macrae F, Walker NI, Jass JR, Young JP
Source: Int J Colorectal Dis, 2010 Jun;25(6), p. 703-12.
EPub date: 2010 Mar 6.
PMID: 20213458
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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.
EPub date: 2009 May 3.
PMID: 19406141
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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 MD, Buchanan DD, Walters R, Roberts A, Arnold S, McKeone D, Clendenning M, Ruszkiewicz AR, Jenkins MA, Hopper JL, Goldblatt J, George J, Suthers GK, Phillips K, Young GP, Macrae F, Drini M, Woods MO, Parry S, Jass JR, Young JP
Source: Fam Cancer, 2009;8(4), p. 313-23.
EPub date: 2009 Feb 25.
PMID: 19241144
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