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Grant Details

Grant Number: 7R01CA108741-04 Interpret this number
Primary Investigator: Pasche, Boris
Organization: University Of Alabama At Birmingham
Project Title: Tgf-Beta Pathway Polymorphisms and Colon Cancer Risk
Fiscal Year: 2008
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Abstract

We have previously identified TGFBR1*6A, a common variant of the TGFBR1 gene, and shown that it transmits TGF-a growth inhibitory signals less effectively than TGFBR1. Our recent meta-analyses show that TGFBR1*6A carriers have a significantly increased risk of colon, breast and ovarian cancer as compared with non-carriers. Overall, cancer risk is increased by 19% among heterozygotes and 70% among homozygotes, a pattern indicative of an allelic dosing effect. We have also shown that TGFBR1*6A may contribute to hereditary colorectal cancer. More than one in eight healthy individuals and one in six patients with cancer is a TGFBR1*6A carrier, which establishes TGFBR1*6A as the first high-frequency low-penetrance candidate tumor susceptibility allele. In contrast, increased TGF-a circulating levels have been associated with a decreased cancer risk in animal models. A common Leucine to Proline substitution at the 10th amino acid position variant within the human TGF- a1 (TGFB1) gene results in higher in vitro extracellular TGFB1 secretion. Carriers of the TGFB1*CC genotype have higher in vivo TGFB1 circulating levels than carriers of the TGFB1*TT genotype. TGFBR1 and TGFB1 variants my have opposite or synergistic effects on colorectal cancer risk. Our central hypothesis is that a combined assessment of the two functionally-relevant TGF- a pathway signaling variants will predict colorectal cancer risk more accurately than each variant alone. The NCI-sponsored familial colorectal cancer registry is an ideal resource in which to test this hypothesis. Using a sibling-matched case-control design we will genotype a total of 4,208 full sibling case-control pairs and First: assess the association between TGFBR1*6A and colorectal cancer. Second: assess the association between TGFB1 and colorectal cancer and perform haplotype analysis of the TGFB1 gene; Third: analyze gene-gene interactions between TGFBR1 and TGFB1. This will explore the relationships between the two functional TGF-a pathway polymorphisms and colorectal risk and determine whether TGF- a signaling, as predicted by these two variants, is associated with colorectal cancer risk; and, Fourth: investigate the relationship between TGF-a pathway polymorphisms and tumor microsatellite instability.

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Publications

Prevention and treatment of cancer with aspirin: where do we stand?
Authors: Pasche B, Wang M, Pennison M, Jimenez H
Source: Semin Oncol, 2014 Jun;41(3), p. 397-401.
EPub date: 2014 Apr 24.
PMID: 25023355
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SMAD4 is a potential prognostic marker in human breast carcinomas.
Authors: Liu NN, Xi Y, Callaghan MU, Fribley A, Moore-Smith L, Zimmerman JW, Pasche B, Zeng Q, Li YL
Source: Tumour Biol, 2014 Jan;35(1), p. 641-50.
EPub date: 2013 Aug 24.
PMID: 23975369
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Potential of whole-genome sequencing for determining risk and personalizing therapy: focus on AML.
Authors: Borate U, Absher D, Erba HP, Pasche B
Source: Expert Rev Anticancer Ther, 2012 Oct;12(10), p. 1289-97.
PMID: 23176617
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TGFBR1 signaling and breast cancer.
Authors: Moore-Smith L, Pasche B
Source: J Mammary Gland Biol Neoplasia, 2011 Jun;16(2), p. 89-95.
EPub date: 2011 Apr 5.
PMID: 21461994
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Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk.
Authors: Kaklamani V, Yi N, Zhang K, Sadim M, Offit K, Oddoux C, Ostrer H, Mantzoros C, Pasche B
Source: Metabolism, 2011 Sep;60(9), p. 1234-43.
EPub date: 2011 Mar 12.
PMID: 21397927
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Bayesian analysis of genetic interactions in case-control studies, with application to adiponectin genes and colorectal cancer risk.
Authors: Yi N, Kaklamani VG, Pasche B
Source: Ann Hum Genet, 2011 Jan;75(1), p. 90-104.
EPub date: 2010 Sep 15.
PMID: 20846215
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Tgf-beta signaling alterations and colon cancer.
Authors: Bellam N, Pasche B
Source: Cancer Treat Res, 2010;155, p. 85-103.
PMID: 20517689
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Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs.
Authors: Pasche B, Wisinski KB, Sadim M, Kaklamani V, Pennison MJ, Zeng Q, Bellam N, Zimmerman J, Yi N, Zhang K, Baron J, Stram DO, Hayes MG
Source: J Exp Clin Cancer Res, 2010 May 25;29, p. 57.
EPub date: 2010 May 25.
PMID: 20500843
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Candidate gene association studies: successes and failures.
Authors: Pasche B, Yi N
Source: Curr Opin Genet Dev, 2010 Jun;20(3), p. 257-61.
EPub date: 2010 Apr 21.
PMID: 20417090
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Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer.
Authors: Adrian K, Strouch MJ, Zeng Q, Barron MR, Cheon EC, Honasoge A, Xu Y, Phukan S, Sadim M, Bentrem DJ, Pasche B, Grippo PJ
Source: Cancer Res, 2009 Dec 15;69(24), p. 9169-74.
PMID: 19951995
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TGFBR1 haplotypes and risk of non-small-cell lung cancer.
Authors: Lei Z, Liu RY, Zhao J, Liu Z, Jiang X, You W, Chen XF, Liu X, Zhang K, Pasche B, Zhang HT
Source: Cancer Res, 2009 Sep 1;69(17), p. 7046-52.
EPub date: 2009 Aug 18.
PMID: 19690145
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One step forward toward identification of the genetic signature of glioblastomas.
Authors: Pasche B, Myers RM
Source: JAMA, 2009 Jul 15;302(3), p. 325-6.
PMID: 19602695
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Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development.
Authors: Zeng Q, Phukan S, Xu Y, Sadim M, Rosman DS, Pennison M, Liao J, Yang GY, Huang CC, Valle L, Di Cristofano A, de la Chapelle A, Pasche B
Source: Cancer Res, 2009 Jan 15;69(2), p. 678-86.
PMID: 19147584
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Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis.
Authors: Varga J, Pasche B
Source: Curr Opin Rheumatol, 2008 Nov;20(6), p. 720-8.
PMID: 18946334
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Role of polymorphisms in Adamantiades-Behçet's disease.
Authors: Kaklamani VG, Sadim M, Koumantaki Y, Kaklamanis P, Pasche B
Source: J Rheumatol, 2008 Dec;35(12), p. 2376-8.
EPub date: 2008 Oct 15.
PMID: 18925687
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Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk.
Authors: Kaklamani VG, Wisinski KB, Sadim M, Gulden C, Do A, Offit K, Baron JA, Ahsan H, Mantzoros C, Pasche B
Source: JAMA, 2008 Oct 1;300(13), p. 1523-31.
PMID: 18827209
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Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer.
Authors: Valle L, Serena-Acedo T, Liyanarachchi S, Hampel H, Comeras I, Li Z, Zeng Q, Zhang HT, Pennison MJ, Sadim M, Pasche B, Tanner SM, de la Chapelle A
Source: Science, 2008 Sep 5;321(5894), p. 1361-5.
EPub date: 2008 Aug 14.
PMID: 18703712
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Familial colorectal cancer: a genetics treasure trove for medical discovery.
Authors: Pasche B
Source: JAMA, 2008 Jun 4;299(21), p. 2564-5.
PMID: 18523226
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Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk.
Authors: Kaklamani VG, Sadim M, Hsi A, Offit K, Oddoux C, Ostrer H, Ahsan H, Pasche B, Mantzoros C
Source: Cancer Res, 2008 May 1;68(9), p. 3178-84.
PMID: 18451143
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Genetics and genomics for clinicians.
Authors: Fontanarosa PB, Pasche B, DeAngelis CD
Source: JAMA, 2008 Mar 19;299(11), p. 1364-5.
PMID: 18349101
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TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation.
Authors: Rosman DS, Phukan S, Huang CC, Pasche B
Source: Cancer Res, 2008 Mar 1;68(5), p. 1319-28.
PMID: 18316594
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Recent advances in breast cancer genetics.
Authors: Pasche B
Source: Cancer Treat Res, 2008;141, p. 1-10.
PMID: 18274079
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Targeting transforming growth factor-beta signaling.
Authors: Pennison M, Pasche B
Source: Curr Opin Oncol, 2007 Nov;19(6), p. 579-85.
PMID: 17906455
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TGF-beta signaling alterations and susceptibility to colorectal cancer.
Authors: Xu Y, Pasche B
Source: Hum Mol Genet, 2007 Apr 15;16 Spec No 1, p. R14-20.
PMID: 17613544
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