TGF-beta polymorphisms and breast cancer in families

Summary

Principal Investigator: Boris Pasche
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.
Funding Period: 2004-12-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc TGF-beta signaling alterations and susceptibility to colorectal cancer
    Yanfei Xu
    Cancer Genetics Program, Division of Hematology Oncology, Department o Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
    Hum Mol Genet 16:R14-20. 2007
  2. pmc TGFBR1 haplotypes and risk of non-small-cell lung cancer
    Zhe Lei
    Laboratory of Medical Genetics, School of Basic Medicine and Biological Sciences, The First Affiliated Hospital, Medical College of Soochow University, Suzhou, PR China
    Cancer Res 69:7046-52. 2009
  3. ncbi Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer
    Kevin Adrian
    Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    Cancer Res 69:9169-74. 2009
  4. pmc Candidate gene association studies: successes and failures
    Boris Pasche
    Division of Hematology Oncology, Department of Medicine, University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL 35294 3300, USA
    Curr Opin Genet Dev 20:257-61. 2010
  5. pmc Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs
    Boris Pasche
    Division of Hematology Oncology, The University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL 35203, USA
    J Exp Clin Cancer Res 29:57. 2010
  6. ncbi Tgf-beta signaling alterations and colon cancer
    Naresh Bellam
    Division of Hematology Oncology, Department of Medicine, UAB Comprehensive Cancer Center, The University of Alabama, Birmingham, AL 35294 3300, USA
    Cancer Treat Res 155:85-103. 2010
  7. pmc Bayesian analysis of genetic interactions in case-control studies, with application to adiponectin genes and colorectal cancer risk
    Nengjun Yi
    Department of Biostatistics, University of Alabama at Birmingham, 35294, USA
    Ann Hum Genet 75:90-104. 2011
  8. pmc Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk
    Virginia Kaklamani
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Metabolism 60:1234-43. 2011
  9. pmc Statistical analysis of genetic interactions
    Nengjun Yi
    Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Genet Res (Camb) 92:443-59. 2010
  10. ncbi TGFBR1 signaling and breast cancer
    Lakisha Moore-Smith
    Division of Hematology Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294 3300, USA
    J Mammary Gland Biol Neoplasia 16:89-95. 2011

Detail Information

Publications30

  1. pmc TGF-beta signaling alterations and susceptibility to colorectal cancer
    Yanfei Xu
    Cancer Genetics Program, Division of Hematology Oncology, Department o Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
    Hum Mol Genet 16:R14-20. 2007
    ....
  2. pmc TGFBR1 haplotypes and risk of non-small-cell lung cancer
    Zhe Lei
    Laboratory of Medical Genetics, School of Basic Medicine and Biological Sciences, The First Affiliated Hospital, Medical College of Soochow University, Suzhou, PR China
    Cancer Res 69:7046-52. 2009
    ..11; 95% CI, 0.03-0.39). This is the first evidence of an association between a TGFBR1 haplotype and risk for NSCLC...
  3. ncbi Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer
    Kevin Adrian
    Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    Cancer Res 69:9169-74. 2009
    ..We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer...
  4. pmc Candidate gene association studies: successes and failures
    Boris Pasche
    Division of Hematology Oncology, Department of Medicine, University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL 35294 3300, USA
    Curr Opin Genet Dev 20:257-61. 2010
    ..Together with genome-wide association studies, candidate gene approaches are likely to fill a large gap in our knowledge of the genetic basis of cancer within the next decade...
  5. pmc Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs
    Boris Pasche
    Division of Hematology Oncology, The University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL 35203, USA
    J Exp Clin Cancer Res 29:57. 2010
    ..This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors...
  6. ncbi Tgf-beta signaling alterations and colon cancer
    Naresh Bellam
    Division of Hematology Oncology, Department of Medicine, UAB Comprehensive Cancer Center, The University of Alabama, Birmingham, AL 35294 3300, USA
    Cancer Treat Res 155:85-103. 2010
    ..This chapter provides an overview of the genetic basis of colorectal cancer and discusses recent discoveries related to alterations in the TGF-beta pathways and their role in the development of colorectal cancer...
  7. pmc Bayesian analysis of genetic interactions in case-control studies, with application to adiponectin genes and colorectal cancer risk
    Nengjun Yi
    Department of Biostatistics, University of Alabama at Birmingham, 35294, USA
    Ann Hum Genet 75:90-104. 2011
    ....
  8. pmc Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk
    Virginia Kaklamani
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Metabolism 60:1234-43. 2011
    ..These findings suggest that variants of the adiponectin pathway may be associated with susceptibility to various forms of common cancers and warrant validation studies...
  9. pmc Statistical analysis of genetic interactions
    Nengjun Yi
    Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Genet Res (Camb) 92:443-59. 2010
    ..I conclude this review by highlighting some areas of future research...
  10. ncbi TGFBR1 signaling and breast cancer
    Lakisha Moore-Smith
    Division of Hematology Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294 3300, USA
    J Mammary Gland Biol Neoplasia 16:89-95. 2011
    ..A better understanding of the molecular mechanism of TGFBR1 signaling in breast cancer may have an impact on breast cancer risk assessment and breast cancer prevention...
  11. pmc The role of the fat mass and obesity associated gene (FTO) in breast cancer risk
    Virginia Kaklamani
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine and Robert H, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 676 N St Clair st suite 850, Chicago, IL 60611, USA
    BMC Med Genet 12:52. 2011
    ..Our objective was to evaluate tissue expression of FTO in breast and the role of FTO SNPs in predicting breast cancer risk...
  12. pmc Potential of whole-genome sequencing for determining risk and personalizing therapy: focus on AML
    Uma Borate
    Division of Hematology Oncology, Department of Medicine, University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL, USA
    Expert Rev Anticancer Ther 12:1289-97. 2012
    ..The holy grail of personalized targeted therapy for the individual AML patient, while minimizing toxicity and prolonging survival, appears closer than ever...
  13. pmc Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development
    Qinghua Zeng
    Department of Medicine, Division of Hematology Oncology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294 3300, USA
    Cancer Res 69:678-86. 2009
    ..These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer...
  14. ncbi Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis
    John Varga
    Department of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
    Curr Opin Rheumatol 20:720-8. 2008
    ..Transforming growth factor-beta (TGF-beta) is required for tissue homeostasis but is also implicated in disease processes including fibrosis, and thus represents a molecular target for therapy...
  15. pmc New insights into breast cancer genetics and impact on patient management
    Diana S Rosman
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
    Curr Treat Options Oncol 8:61-73. 2007
    ..In the next decade, screening for combinations of high and low penetrance genes will likely permit the identification of a large fraction of inherited breast cancer cases and will further reduce the burden of familial breast cancer...
  16. pmc Genetics and genomics: a call for papers
    Catherine D DeAngelis
    Arch Surg 142:822. 2007
  17. pmc Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development
    Yansong Bian
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
    Hum Mol Genet 16:3128-35. 2007
    ..They also represent the first human report of somatically acquired altered stromal TGF-beta signaling during oncogenesis and the first report of a concordant mutation in the stromal and epithelial compartments in colon cancer...
  18. pmc Targeting transforming growth factor-beta signaling
    Michael Pennison
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Curr Opin Oncol 19:579-85. 2007
    ..The current review focuses on the recent advances made in this area, and the potential of these strategies in the clinical treatment of cancer and fibrosis...
  19. pmc Recent advances in breast cancer genetics
    Boris Pasche
    Department of Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern University Cancer Genetics Program, Chicago, IL 60611, USA
    Cancer Treat Res 141:1-10. 2008
  20. pmc TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation
    Diana S Rosman
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St Clair Street, Suite 880, Chicago, IL 60611, USA
    Cancer Res 68:1319-28. 2008
    ..These results provide the first evidence that TGFBR1*6A may contribute to cancer progression in a TGF-beta signaling-independent manner...
  21. pmc Genetics and genomics for clinicians
    Phil B Fontanarosa
    JAMA 299:1364-5. 2008
  22. pmc Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk
    Virginia G Kaklamani
    Division of Hematology Oncology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Cancer Res 68:3178-84. 2008
    ..89; P(trend) = 0.001). This is the first report of an association between functionally relevant variants of the adiponectin pathway and breast cancer risk. The results warrant further studies of the adiponectin pathway in breast cancer...
  23. pmc Familial colorectal cancer: a genetics treasure trove for medical discovery
    Boris Pasche
    JAMA 299:2564-5. 2008
  24. pmc No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study
    Timothy R Rebbeck
    Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6021, USA
    Breast Cancer Res Treat 115:185-92. 2009
    ..The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population...
  25. pmc Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer
    Laura Valle
    Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
    Science 321:1361-5. 2008
    ..Conservative estimates suggest that ASE confers a substantially increased risk of CRC (odds ratio, 8.7; 95% confidence interval, 2.6 to 29.1), but these estimates require confirmation and will probably show ethnic differences...
  26. pmc Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk
    Virginia G Kaklamani
    Cancer Genetics Program, Division of Hematology and Oncology, Department of Medicine and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    JAMA 300:1523-31. 2008
    ..While there is evidence of an association between circulating adiponectin levels and colorectal cancer risk, no association between genes of the adiponectin pathway and colorectal cancer have been reported to date...
  27. pmc Role of polymorphisms in Adamantiades-Behçet's disease
    Virginia G Kaklamani
    Cancer Genetics Program, Division of Hematology Oncology, Department of Medicine, and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
    J Rheumatol 35:2376-8. 2008
    ..We tested whether incidence of these polymorphisms would differ in patients with A-BD compared with healthy controls of similar age and geographic location...
  28. pmc TGF-β: duality of function between tumor prevention and carcinogenesis
    Daniel R Principe
    Affiliations of authors Department of Medicine, Division of Gastroenterology DRP, JB, BJ and Division of Hematology Oncology HGM, Department of Surgery, Division of GI Surgical Oncology DRP, PJG, and Department of Urology CL, Northwestern University Feinberg School of Medicine, Chicago, IL Department of Biomedical Engineering McCormick School of Engineering, Northwestern University, Evanston, IL DRP Department of Biomedical Sciences, University of Wisconsin Milwaukee, Milwaukee, WI JAD UMR INSERM U1052, CNRS 5286, Universite Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France LB Division of Hematology Oncology, Department of Medicine, University of Alabama Birmingham, Birmingham, AL BP Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA CL
    J Natl Cancer Inst 106:djt369. 2014
    ..Understanding the mechanisms of TGF-β dysregulation will likely reveal novel points of convergence between TGF-β and other pathways that can be specifically targeted for therapy. ..

Research Grants30

  1. Consortium Study to Identify Breast Cancer Susceptibility Loci
    Wei Zheng; Fiscal Year: 2013
    ..This study will generate valuable results for the identification of high-risk women for the primary and secondary prevention of breast cancer. ..
  2. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  3. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
  4. Inherited genetic factors in breast cancer predisposition and tumor presentation
    Julie Dutil; Fiscal Year: 2013
    ..Massey is an expert in bioinformatics applied to genomic data;Dr. Schabath is a cancer genetic epidemiologist;and Dr Ziv is a leader in the field of breast cancer admixture mapping. ..
  5. Vitamin D, Related Genes and Breast Cancer Risk
    Anne Zeleniuch-Jacquotte; Fiscal Year: 2013
    ..Circulating levels of estradiol will be measured in postmenopausal matched sets. ..
  6. Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)
    Thomas A Sellers; Fiscal Year: 2013
    ..g., mucinous and clear cell). ..
  7. Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors
    Darell D Bigner; Fiscal Year: 2013
    ..abstract_text> ..
  8. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..