|Grant Number:||5R01CA040641-21 Interpret this number|
|Primary Investigator:||Burt, Randall|
|Organization:||University Of Utah|
|Project Title:||High Risk Familial Colon Cancer Genetics and Phenotype|
DESCRIPTION (provided by applicant): Genetic, clinical and molecular characterization of inherited colon cancer risk is the focus of our present and long-term work. Genes for the rare syndromes of this malignancy have been found but account for only a small fraction of the estimated one-third of colon cancer cases that arise from inheritance. The aims of our present proposal are 1) to identify the susceptibility genes that give rise to the more common inherited risk, 2) to continue to define the associated phenotype, 3) to establish molecular characteristics of the high-risk families and known syndromes with gene expression profiling and 4) to examine the expression of specific APC/beta-catenin pathway genes as potential diagnostic markers. Together these goals will provide tools to identify persons with inherited risk. We will accomplish the aims as follows: We will identify colon cancer susceptibility loci by linkage analysis of large high-risk colon cancer families in which the known syndromes of colon cancer have been ruled out. Colonoscopy is performed on family members to define polyp expression, both for phenotype and linkage analysis. Gene expression profiling by microarray analysis is performed on normal appearing and neoplastic colonic tissue obtained at colonoscopy and immediately preserved. Profiling will assist both in identification of susceptibility pathways and in establishing characteristic expression profiles in the inherited colon cancer settings. Gene expression patterns will be examined in the normal and neoplastic tissue of the high-risk families and compared to similar samples from families with familial adenomatous polyposis (FAP), attenuated FAP, hereditary nonpolyposis colorectal cancer, sporadic adenomatous polyp cases and normal controls. Gene expression will be examined using a reference RNA and analyzed by supervised (and later unsupervised) analysis of the groups. Finally the expression of four specific APC/beta-catenin pathway marker genes will be examined in neoplastic and normal tissues from the above groups by both real-time quantitative PCR and by in situ RNA hybridization. Previous microarray experiments in our laboratory indicate that expression of these genes is frequently perturbed in sporadic polyps, making them attractive markers of cancer susceptibility to evaluate APC/beta-catenin pathway contributions in undefined forms of inherited colon cancer, as compared to defined inherited syndromes.
Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk.
Authors: Taylor DP, Cannon-Albright LA, Sweeney C, Williams MS, Haug PJ, Mitchell JA, Burt RW
Source: Genet Med, 2011 Aug;13(8), p. 737-43.
How well does family history predict who will get colorectal cancer? Implications for cancer screening and counseling.
Authors: Taylor DP, Stoddard GJ, Burt RW, Williams MS, Mitchell JA, Haug PJ, Cannon-Albright LA
Source: Genet Med, 2011 May;13(5), p. 385-91.
Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer.
Authors: Neklason DW, Tuohy TM, Stevens J, Otterud B, Baird L, Kerber RA, Samowitz WS, Kuwada SK, Leppert MF, Burt RW
Source: J Med Genet, 2010 Oct;47(10), p. 692-9.
EPub date: 2010 Jun 3.
Parental attitudes, beliefs, and perceptions about genetic testing for FAP and colorectal cancer surveillance in minors.
Authors: Levine FR, Coxworth JE, Stevenson DA, Tuohy T, Burt RW, Kinney AY
Source: J Genet Couns, 2010 Jun;19(3), p. 269-79.
EPub date: 2010 Mar 2.
Population-based family history-specific risks for colorectal cancer: a constellation approach.
Authors: Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA
Source: Gastroenterology, 2010 Mar;138(3), p. 877-85.
EPub date: 2009 Dec 21.
Colonic adenoma risk in familial colorectal cancer--a study of six extended kindreds.
Authors: Neklason DW, Thorpe BL, Ferrandez A, Tumbapura A, Boucher K, Garibotti G, Kerber RA, Solomon CH, Samowitz WS, Fang JC, Mineau GP, Leppert MF, Burt RW, Kuwada SK
Source: Am J Gastroenterol, 2008 Oct;103(10), p. 2577-84.
EPub date: 2008 Jul 30.
Can we identify the high-risk patients to be screened? A genetic approach.
Authors: Gammon A, Kohlmann W, Burt R
Source: Digestion, 2007;76(1), p. 7-19.
EPub date: 2007 Oct 19.
Colorectal cancer surveillance behaviors among members of typical and attenuated FAP families.
Authors: Kinney AY, Hicken B, Simonsen SE, Venne V, Lowstuter K, Balzotti J, Burt RW
Source: Am J Gastroenterol, 2007 Jan;102(1), p. 153-62.
Disease-associated casein kinase I delta mutation may promote adenomatous polyps formation via a Wnt/beta-catenin independent mechanism.
Authors: Tsai IC, Woolf M, Neklason DW, Branford WW, Yost HJ, Burt RW, Virshup DM
Source: Int J Cancer, 2007 Mar 1;120(5), p. 1005-12.
Extracolonic cancers associated with hereditary nonpolyposis colorectal cancer in the Utah Population Database.
Authors: Maul JS, Warner NR, Kuwada SK, Burt RW, Cannon-Albright LA
Source: Am J Gastroenterol, 2006 Jul;101(7), p. 1591-6.
Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database.
Authors: Kerber RA, Neklason DW, Samowitz WS, Burt RW
Source: Fam Cancer, 2005;4(3), p. 239-44.
Genetic testing for inherited colon cancer.
Authors: Burt R, Neklason DW
Source: Gastroenterology, 2005 May;128(6), p. 1696-716.
Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis.
Authors: Burt RW, Leppert MF, Slattery ML, Samowitz WS, Spirio LN, Kerber RA, Kuwada SK, Neklason DW, Disario JA, Lyon E, Hughes JP, Chey WY, White RL
Source: Gastroenterology, 2004 Aug;127(2), p. 444-51.
Intron 4 mutation in APC gene results in splice defect and attenuated FAP phenotype.
Authors: Neklason DW, Solomon CH, Dalton AL, Kuwada SK, Burt RW
Source: Fam Cancer, 2004;3(1), p. 35-40.
The inducible prostaglandin biosynthetic enzyme, cyclooxygenase 2, is not mutated in patients with attenuated adenomatous polyposis coli.
Authors: Spirio LN, Dixon DA, Robertson J, Robertson M, Barrows J, Traer E, Burt RW, Leppert MF, White R, Prescott SM
Source: Cancer Res, 1998 Nov 1;58(21), p. 4909-12.
Genetic heterogeneity and unmapped genes for colorectal cancer.
Authors: Lewis CM, Neuhausen SL, Daley D, Black FJ, Swensen J, Burt RW, Cannon-Albright LA, Skolnick MH
Source: Cancer Res, 1996 Mar 15;56(6), p. 1382-8.
Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.
Authors: Spirio LN, Kutchera W, Winstead MV, Pearson B, Kaplan C, Robertson M, Lawrence E, Burt RW, Tischfield JA, Leppert MF, Prescott SM, White R
Source: Cancer Res, 1996 Mar 1;56(5), p. 955-8.
Familial risk and colon cancer.
Authors: Burt RW
Source: Int J Cancer, 1996 Feb 20;69(1), p. 44-6.
The nonspecificity of histological findings reported for flat adenomas.
Authors: Samowitz WS, Burt RL
Source: Hum Pathol, 1995 May;26(5), p. 571-3.
The gene for familial polyposis coli maps to the long arm of chromosome 5.
Authors: Leppert M, Dobbs M, Scambler P, O'Connell P, Nakamura Y, Stauffer D, Woodward S, Burt R, Hughes J, Gardner E
Source: Science, 1987 Dec 4;238(4832), p. 1411-3.
Villous adenoma of the duodenal papilla presenting as necrotizing pancreatitis in a patient with Gardner's syndrome.
Authors: Burt RW, Rikkers LF, Gardner EJ, Lee RG, Tolman KG
Source: Gastroenterology, 1987 Feb;92(2), p. 532-5.