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Grant Details

Grant Number: 3R01CA098932-05S1 Interpret this number
Primary Investigator: Manne, Upender
Organization: University Of Alabama At Birmingham
Project Title: Prognostic Molecular Markers of Colorectal Cancer
Fiscal Year: 2009
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Abstract

The overall goal of this proposal is to identify potential prognostic markers of colorectal adenocarcinoma (CRC). Despite numerous published studies on prognostic markers of CRC, no new marker has achieved accepted clinical utility due to controversial results. Recent studies to resolve some of the controversies, from the laboratories of others and ours, have suggested that prognostic value of several molecular and phenotypic features of CRCs vary with anatomic location of the tumor and/or with patient race/ethnicity. Therefore, we propose to identify the molecular markers of sporadic CRCs that are associated with aggressiveness of the tumor hence prognosis of African-American and Caucasian patients. Since the comprehensive evaluation of vast amounts of data requires powerful statistical techniques, we propose to use knowledge discovery tools to identify potentially useful information to predict patient prognosis. In Specific Aim 1, stage-and site-matched 750 CRC patient populations each, of African-Americans and Caucasians will be evaluated for phenotypic expression of several key molecular markers which are likely to be acceptable as prognosticators. The markers to be analyzed immunohistochemically (IHC) are: DCC (deleted in colon cancer), p53, p21waf-1, p27Kip-1, Mdm2, cyclin E, Ki67, Bcl-2, Bax, MUC1, cyclooxygenase 2, and thymidylate synthase. The extent of apoptosis will be determined utilizing TUNEL. In Specific Aim 2, DNA extracted from archival tissues will be analyzed for microsatellite instability (MSI) at 4 CA-dinucleotide MS loci (Mfd27, Mfd41, Mfd47, and Mfd57) and 2 poly-A repeats (BAT25, BAT26). In addition, the tissue array sections will be evaluated for the expression of hMLH1 and hMSH2 to determine DNA mismatch repair deficient tumors. The phenotypic variations and the level of MSI will be correlated with the prognosis of African-Americans and Caucasians based on the anatomic location of the tumor using statistical methods. In Specific Aim 3, we will use data mining tools to identify the complex relationships of multiple factors in data sets generated in Specific Aims 1 and 2. Eventually, separate prognostic models will be developed for African-American and Caucasian patients with CRC. The findings of these studies will aid the clinical oncologist in identifying aggressive forms of CRCs using MSI and phenotypic patterns, and help in selecting potential candidates for therapeutic interventions. Additionally, these strategies can be used to identify key information or decision making knowledge discoveries in vast molecular epidemiological databases that are already generated.

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Publications

Prognostic significance and gene expression profiles of p53 mutations in microsatellite-stable stage III colorectal adenocarcinomas.
Authors: Katkoori VR, Shanmugam C, Jia X, Vitta SP, Sthanam M, Callens T, Messiaen L, Chen D, Zhang B, Bumpers HL, Samuel T, Manne U
Source: PLoS One, 2012;7(1), p. e30020.
EPub date: 2012 Jan 19.
PMID: 22276141
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Development and progression of colorectal neoplasia.
Authors: Manne U, Shanmugam C, Katkoori VR, Bumpers HL, Grizzle WE
Source: Cancer Biomark, 2010;9(1-6), p. 235-65.
PMID: 22112479
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Evaluation of lymph node numbers for adequate staging of Stage II and III colon cancer.
Authors: Shanmugam C, Hines RB, Jhala NC, Katkoori VR, Zhang B, Posey JA Jr, Bumpers HL, Grizzle WE, Eltoum IE, Siegal GP, Manne U
Source: J Hematol Oncol, 2011 May 28;4, p. 25.
EPub date: 2011 May 28.
PMID: 21619690
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Development of combination tapered fiber-optic biosensor dip probe for quantitative estimation of interleukin-6 in serum samples.
Authors: Wang CW, Manne U, Reddy VB, Oelschlager DK, Katkoori VR, Grizzle WE, Kapoor R
Source: J Biomed Opt, 2010 Nov-Dec;15(6), p. 067005.
PMID: 21198209
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Prognostic value of mucin 4 expression in colorectal adenocarcinomas.
Authors: Shanmugam C, Jhala NC, Katkoori VR, Wan W, Meleth S, Grizzle WE, Manne U
Source: Cancer, 2010 Aug 1;116(15), p. 3577-86.
PMID: 20564074
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Comparison of the predictive qualities of three prognostic models of colorectal cancer.
Authors: Anderson B, Hardin JM, Alexander DD, Grizzle WE, Meleth S, Manne U
Source: Front Biosci (Elite Ed), 2010 Jun 1;2, p. 849-56.
EPub date: 2010 Jun 1.
PMID: 20515758
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Effect of comorbidity and body mass index on the survival of African-American and Caucasian patients with colon cancer.
Authors: Hines RB, Shanmugam C, Waterbor JW, McGwin G Jr, Funkhouser E, Coffey CS, Posey J, Manne U
Source: Cancer, 2009 Dec 15;115(24), p. 5798-806.
PMID: 19937953
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Predictive capacity of three comorbidity indices in estimating mortality after surgery for colon cancer.
Authors: Hines RB, Chatla C, Bumpers HL, Waterbor JW, McGwin G Jr, Funkhouser E, Coffey CS, Posey J, Manne U
Source: J Clin Oncol, 2009 Sep 10;27(26), p. 4339-45.
EPub date: 2009 Aug 3.
PMID: 19652054
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Prognostic significance of p53 codon 72 polymorphism differs with race in colorectal adenocarcinoma.
Authors: Katkoori VR, Jia X, Shanmugam C, Wan W, Meleth S, Bumpers H, Grizzle WE, Manne U
Source: Clin Cancer Res, 2009 Apr 1;15(7), p. 2406-16.
PMID: 19339276
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Immunohistochemical expression of rabphilin-3A-like (Noc2) in normal and tumor tissues of human endocrine pancreas.
Authors: Shanmugam C, Katkoori VR, Jhala NC, Grizzle WE, Manne U
Source: Biotech Histochem, 2009 Apr;84(2), p. 39-45.
PMID: 19212825
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Clinical significance of a novel single nucleotide polymorphism in the 5' untranslated region of the Rabphillin-3A-Like gene in colorectal adenocarcinoma.
Authors: Katkoori VR, Jia X, Chatla C, Kumar S, Ponnazhagan S, Callens T, Messiaen L, Grizzle WE, Manne U
Source: Front Biosci, 2008 Jan 1;13, p. 1050-61.
EPub date: 2008 Jan 1.
PMID: 17981610
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Recurrence and survival predictive value of phenotypic expression of Bcl-2 varies with tumor stage of colorectal adenocarcinoma.
Authors: Chatla C, Jhala NC, Katkoori VR, Alexander D, Meleth S, Grizzle WE, Manne U
Source: Cancer Biomark, 2005;1(4-5), p. 241-50.
PMID: 17192048
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High-grade tumor differentiation is an indicator of poor prognosis in African Americans with colonic adenocarcinomas.
Authors: Alexander D, Jhala N, Chatla C, Steinhauer J, Funkhouser E, Coffey CS, Grizzle WE, Manne U
Source: Cancer, 2005 May 15;103(10), p. 2163-70.
PMID: 15816050
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Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage.
Authors: Manne U, Jhala NC, Jones J, Weiss HL, Chatla C, Meleth S, Suarez-Cuervo C, Grizzle WE
Source: Clin Cancer Res, 2004 Mar 1;10(5), p. 1743-52.
PMID: 15014027
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