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Grant Details

Grant Number: 5R01CA112520-09 Interpret this number
Primary Investigator: Pasche, Boris
Organization: University Of Alabama At Birmingham
Project Title: Tgf-Beta Polymorphisms and Breast Cancer in Families
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): The Transforming Growth Factor Beta (TGF-ss) superfamily of growth factors regulates many cellular functions including cell growth, adhesion, migration, cell-fate determination and differentiation, and apoptosis. Ligands of the TGF-ss superfamily of growth factors comprises several TGF-ss isoforms, Activin isoforms, and Bone Morphogenetic Proteins, which are encoded by different genes but function through a similar receptor signaling system. The functionality of ligands, receptor proteins and SMAD intracellular messengers is critical for inhibitory signal transduction. There is, in this respect, growing evidence suggesting that common variants of the ligands, receptors and intracellular messengers of the TGF-ss superfamily may significantly modify breast cancer risk and outcome. We were the first to identify TGFBR1*6A, a common variant of the TGFBR1 gene. Our meta-analysis of fourteen case-control studies that included 6694 breast cancer cases and 8579 controls shows that TGFBR1*6A carriers have a significantly increased risk of breast cancer as compared with non- carriers. Overall, breast cancer risk is higher among TGFBR1*6A homozygotes (O.R. 1.40, 95% CI 1.04-1.88) than among TGFBR1*6A heterozygotes (O.R. 1.12, 95% CI 1.00-1.25) (Ptrend =8.41 x 10-4). A common variant of the TGFB1 gene has been associated with higher circulating levels of TGF-2 and increased TGF-ss secretion in vitro. A recent study conducted by the Breast Cancer Association Consortium (BCAC) has shown that breast cancer risk was increased among TGFB1 L10P heterozygotes (O.R. 1.07, 95% CI 1.02-1.13) and homozygotes (O.R. 1.16, 95% CI 1.08-1.25) (Ptrend = 2.8 x 10-5). Hence, naturally-occurring variants encoding for one ligand (TGFB1) and one receptor (TGFBR1) from the same signaling pathway are associated with breast cancer risk. These combined findings provide a strong rationale to comprehensively assess the TGF-2 signaling pathway in breast cancer. We propose to assess the association between haplotypes of the 65 genes of the TGF-2 superfamily and breast cancer risk using a family-based association study. Overall, we will perform a comprehensive genotypic analysis of the pathway in 5357 sister cases and sister controls from the NCI-sponsored Breast Cancer Family Registry. Genetic variants associated with breast cancer risk will be validated using the resources of BCAC. Validated SNPs will be further examined by the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. To search for the causal variant(s) we will 1) re-sequence the validated region(s) in 200 patients that carry the risk haplotypes, 2) perform dense SNP genotyping. Using RNA extracted from lymphoblastoid cell lines we will functionally characterize the putative functionally-relevant SNPs independently and jointly. In secondary analyses, we will evaluate whether the associations of the various haplotypes and functionally-relevant mutations with breast cancer risk differ according to tumor stage, ER/PR and ERBB2 status and menopausal status. We will also determine the association of the TGF-2 superfamily SNPs with breast cancer outcomes. PUBLIC HEALTH RELEVANCE: There is growing evidence that subtle changes in genes of the TGF-2 pathway modify breast cancer risk. This project will study 65 genes of the TGF-2 pathway in 5357 women with breast cancer and their unaffected sisters and determine which genes are associated with breast cancer risk.

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Publications

TGFBR1 and cancer susceptibility.
Authors: Pasche B, Pennison MJ, Jimenez H, Wang M
Source: Trans Am Clin Climatol Assoc, 2014;125, p. 300-12.
PMID: 25125747
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TGF-?: duality of function between tumor prevention and carcinogenesis.
Authors: Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, Pasche B, Lee C, Grippo PJ
Source: J Natl Cancer Inst, 2014 Feb;106(2), p. djt369.
PMID: 24511106
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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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Whole-genome sequencing: a step closer to personalized medicine.
Authors: Pasche B, Absher D
Source: JAMA, 2011 Apr 20;305(15), p. 1596-7.
PMID: 21505140
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The role of the fat mass and obesity associated gene (FTO) in breast cancer risk.
Authors: Kaklamani V, Yi N, Sadim M, Siziopikou K, Zhang K, Xu Y, Tofilon S, Agarwal S, Pasche B, Mantzoros C
Source: BMC Med Genet, 2011 Apr 13;12, p. 52.
EPub date: 2011 Apr 13.
PMID: 21489227
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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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Statistical analysis of genetic interactions.
Authors: Yi N
Source: Genet Res (Camb), 2010 Dec;92(5-6), p. 443-59.
PMID: 21429274
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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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No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study.
Authors: Rebbeck TR, Antoniou AC, Llopis TC, Nevanlinna H, Aittomäki K, Simard J, Spurdle AB, KConFab, Couch FJ, Pereira LH, Greene MH, Andrulis IL, Ontario Cancer Genetics Network, Pasche B, Kaklamani V, Breast Cancer Family Registry, Hamann U, Szabo C, Peock S, Cook M, Harrington PA, Donaldson A, Male AM, Gardiner CA, Gregory H, Side LE, Robinson AC, Emmerson L, Ellis I, EMBRACE, Peyrat JP, Fournier J, Vennin P, Adenis C, Muller D, Fricker JP, Longy M, Sinilnikova OM, Stoppa-Lyonnet D, GEMO, Schmutzler RK, Versmold B, Engel C, Meindl A, Kast K, Schaefer D, Froster UG, Chenevix-Trench G, Easton DF
Source: Breast Cancer Res Treat, 2009 May;115(1), p. 185-92.
EPub date: 2008 Jun 4.
PMID: 18523885
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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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Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development.
Authors: Bian Y, Knobloch TJ, Sadim M, Kaklamani V, Raji A, Yang GY, Weghorst CM, Pasche B
Source: Hum Mol Genet, 2007 Dec 15;16(24), p. 3128-35.
EPub date: 2007 Sep 21.
PMID: 17890272
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Genetics and genomics: a call for papers.
Authors: DeAngelis CD, Fontanarosa PB, King MC, Pasche B
Source: Arch Surg, 2007 Sep;142(9), p. 822.
PMID: 17875835
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New insights into breast cancer genetics and impact on patient management.
Authors: Rosman DS, Kaklamani V, Pasche B
Source: Curr Treat Options Oncol, 2007 Feb;8(1), p. 61-73.
PMID: 17634833
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