Grant Number:	5R01CA050468-18 Interpret this number
Primary Investigator:	Dupont, William
Organization:	Vanderbilt University
Project Title:	Epidemiology of Molecular Risk Factors for Breast Cancer
Fiscal Year:	2009

DESCRIPTION (provided by applicant): We propose to study molecular, genetic and histologic markers of breast cancer risk in women with benign breast disease. We will use a unique cohort of such women to pursue the following Specific Aims: 1. To determine the effects on breast cancer risk of the 6A polymorphism of the transforming growth factor beta type I receptor (T(3R-I). We will also study how expression levels of the TpR-l, and its principal substrate Smad2, affect breast cancer risk in women with proliferative breast lesions. 2. To evaluate the combined influence on breast cancer risk of benign breast lesions and 424 single nucleotide polymorphisms (SNPs) from 86 candidate genes involved in estrogen biosynthesis, function and oxidative metabolism. Cross-sectional analyses will also be performed that examine how specific genotypes are correlated with different types of benign breast disease. These studies will explore potential influences on breast cancer risk of ER-mediated cell proliferation or the generation of oxidative estrogen metabolites that may damage DNA. 3. To expand the size and length of follow-up of our study cohort. The research will be based on a large retrospective cohort study of women who underwent benign breast biopsy between 1954 and 1995. Paraffin-embedded tissue from the entry biopsy of these patients is available. By the end of this project we estimate that we will have observed 890 breast cancer cases during follow-up among the 11,547 members of this cohort. We will conduct a series of nested case- control studies on these women. The 890 breast cancer cases will be matched by race, age and year of their benign breast biopsy to 1780 controls (1:2 ratio). Genotyping will be performed using the Illumina GoldenGate assay while immunohistochemical methods will be used to identify abnormal protein expression. We will use supervised principal component analyses to assess the individual and combined effects of molecular, histologic and epidemiologic variables on breast cancer risk. A false discovery rate (FDR) approach will be used to identify promising findings that will be subject to validation in other data sets. This project takes advantage of an established cohort of women with biopsy-confirmed benign breast disease. Clinical, demographic, and histologic information, as well as genomic DNA is uniformly available. This project will permit the combination of modern methods in molecular biology, genetics, pathology and epidemiology to assess potentially powerful new markers of breast cancer progression and prognosis. We expect that it will lead to important advances in the prevention and treatment of this disease.




Interchromosomal Translocations as a Means to Map Chromosome Territories in Breast Cancer.
Authors: Parl F.F. , Dupont W.D. , Crooke P.S. .
Source: Cancer Informatics, 2019; 18, p. 1176935119842573.
EPub date: 2019-04-16 00:00:00.0.
PMID: 31019364
Related Citations

Genomic-Epidemiologic Evidence that Estrogens Promote Breast Cancer Development.
Authors: Parl F.F. , Crooke P.S. , Plummer W.D. , Dupont W.D. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2018-05-22 00:00:00.0; , .
EPub date: 2018-05-22 00:00:00.0.
PMID: 29789325
Related Citations

Breast cancer risk by the extent and type of atypical hyperplasia.
Authors: Degnim A.C. , Visscher D.W. , Radisky D.C. , Frost M.H. , Vierkant R.A. , Frank R.D. , Winham S.J. , Vachon C.M. , Dupont W.D. , Hartmann L.C. .
Source: Cancer, 2016 Oct; 122(19), p. 3087-8.
EPub date: 2016-06-28 00:00:00.0.
PMID: 27352099
Related Citations

Extent Of Atypical Hyperplasia Stratifies Breast Cancer Risk In 2 Independent Cohorts Of Women
Authors: Degnim A.C. , Dupont W.D. , Radisky D.C. , Vierkant R.A. , Frank R.D. , Frost M.H. , Winham S.J. , Sanders M.E. , Smith J.R. , Page D.L. , et al. .
Source: Cancer, 2016-06-28 00:00:00.0; , .
PMID: 27352219
Related Citations

Continued Observation Of The Natural History Of Low-grade Ductal Carcinoma In Situ Reaffirms Proclivity For Local Recurrence Even After More Than 30 Years Of Follow-up
Authors: Sanders M.E. , Schuyler P.A. , Simpson J.F. , Page D.L. , Dupont W.D. .
Source: Modern Pathology : An Official Journal Of The United States And Canadian Academy Of Pathology, Inc, 2015 May; 28(5), p. 662-9.
PMID: 25502729
Related Citations

Atypical Hyperplasia Of The Breast--risk Assessment And Management Options
Authors: Hartmann L.C. , Degnim A.C. , Santen R.J. , Dupont W.D. , Ghosh K. .
Source: The New England Journal Of Medicine, 2015-01-01 00:00:00.0; 372(1), p. 78-89.
PMID: 25551530
Related Citations

A Multistage Genetic Association Study Identifies Breast Cancer Risk Loci At 10q25 And 16q24
Authors: Higginbotham K.S. , Breyer J.P. , McReynolds K.M. , Bradley K.M. , Schuyler P.A. , Plummer W.D. , Freudenthal M.E. , Trentham-Dietz A. , Newcomb P.A. , Parl F.F. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2012 Sep; 21(9), p. 1565-73.
PMID: 22806168
Related Citations

Clinicopathologic Characteristics Of Carcinomas That Develop After A Biopsy Containing Columnar Cell Lesions: Evidence Against A Precursor Role
Authors: Boulos F.I. , Dupont W.D. , Schuyler P.A. , Sanders M.E. , Page D.L. , Fedda F.A. , Simpson J.F. .
Source: Cancer, 2012-05-01 00:00:00.0; 118(9), p. 2372-7.
PMID: 21918964
Related Citations

Estrogen Metabolism And Exposure In A Genotypic-phenotypic Model For Breast Cancer Risk Prediction
Authors: Crooke P.S. , Justenhoven C. , Brauch H. , GENICA Consortium , Dawling S. , Roodi N. , Higginbotham K.S. , Plummer W.D. , Schuyler P.A. , Sanders M.E. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2011 Jul; 20(7), p. 1502-15.
PMID: 21610218
Related Citations

A Multistage Association Study Identifies A Breast Cancer Genetic Locus At Ncoa7
Authors: Higginbotham K.S. , Breyer J.P. , Bradley K.M. , Schuyler P.A. , Plummer W.D. , Freudenthal M.E. , Trentham-Dietz A. , Newcomb P.A. , Sanders M.E. , Page D.L. , et al. .
Source: Cancer Research, 2011-06-01 00:00:00.0; 71(11), p. 3881-8.
PMID: 21610108
Related Citations

Protein Phosphatase 2a Subunit Gene Haplotypes And Proliferative Breast Disease Modify Breast Cancer Risk
Authors: Dupont W.D. , Breyer J.P. , Bradley K.M. , Schuyler P.A. , Plummer W.D. , Sanders M.E. , Page D.L. , Smith J.R. .
Source: Cancer, 2010-01-01 00:00:00.0; 116(1), p. 8-19.
PMID: 19890961
Related Citations

Heritable variation of ERBB2 and breast cancer risk.
Authors: Breyer J.P. , Sanders M.E. , Airey D.C. , Cai Q. , Yaspan B.L. , Schuyler P.A. , Dai Q. , Boulos F. , Olivares M.G. , Bradley K.M. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Apr; 18(4), p. 1252-8.
PMID: 19336545
Related Citations

Histologic Associations And Long-term Cancer Risk In Columnar Cell Lesions Of The Breast: A Retrospective Cohort And A Nested Case-control Study
Authors: Boulos F.I. , Dupont W.D. , Simpson J.F. , Schuyler P.A. , Sanders M.E. , Freudenthal M.E. , Page D.L. .
Source: Cancer, 2008-11-01 00:00:00.0; 113(9), p. 2415-21.
PMID: 18816618
Related Citations

Ethnic And Genetic Determinants Of Cardiovascular Response To The Selective Alpha 2-adrenoceptor Agonist Dexmedetomidine
Authors: Kurnik D. , Muszkat M. , Sofowora G.G. , Friedman E.A. , Dupont W.D. , Scheinin M. , Wood A.J. , Stein C.M. .
Source: Hypertension, 2008 Feb; 51(2), p. 406-11.
PMID: 18071056
Related Citations

Excellent Survival, Cancer Type, And Nottingham Grade After Atypical Lobular Hyperplasia On Initial Breast Biopsy
Authors: McLaren B.K. , Schuyler P.A. , Sanders M.E. , Jensen R.A. , Simpson J.F. , Dupont W.D. , Page D.L. .
Source: Cancer, 2006-09-15 00:00:00.0; 107(6), p. 1227-33.
PMID: 16894523
Related Citations

Interdependence Of Radial Scar And Proliferative Disease With Respect To Invasive Breast Carcinoma Risk In Patients With Benign Breast Biopsies
Authors: Sanders M.E. , Page D.L. , Simpson J.F. , Schuyler P.A. , Dale Plummer W. , Dupont W.D. .
Source: Cancer, 2006-04-01 00:00:00.0; 106(7), p. 1453-61.
PMID: 16502407
Related Citations

The Natural History Of Low-grade Ductal Carcinoma In Situ Of The Breast In Women Treated By Biopsy Only Revealed Over 30 Years Of Long-term Follow-up
Authors: Sanders M.E. , Schuyler P.A. , Dupont W.D. , Page D.L. .
Source: Cancer, 2005-06-15 00:00:00.0; 103(12), p. 2481-4.
PMID: 15884091
Related Citations

The Impact Of Peer Management On Test-ordering Behavior
Authors: Neilson E.G. , Johnson K.B. , Rosenbloom S.T. , Dupont W.D. , Talbert D. , Giuse D.A. , Kaiser A. , Miller R.A. , Resource Utilization Committee .
Source: Annals Of Internal Medicine, 2004-08-03 00:00:00.0; 141(3), p. 196-204.
PMID: 15289216
Related Citations

Association Of Homozygous Wild-type Glutathione S-transferase M1 Genotype With Increased Breast Cancer Risk
Authors: Roodi N. , Dupont W.D. , Moore J.H. , Parl F.F. .
Source: Cancer Research, 2004-02-15 00:00:00.0; 64(4), p. 1233-6.
PMID: 14973116
Related Citations

Atypical Lobular Hyperplasia As A Unilateral Predictor Of Breast Cancer Risk: A Retrospective Cohort Study
Authors: Page D.L. , Schuyler P.A. , Dupont W.D. , Jensen R.A. , Plummer W.D. , Simpson J.F. .
Source: Lancet (london, England), 2003-01-11 00:00:00.0; 361(9352), p. 125-9.
PMID: 12531579
Related Citations

Loss Of Expression Of Transforming Growth Factor Beta Type Ii Receptor Correlates With High Tumour Grade In Human Breast In-situ And Invasive Carcinomas
Authors: Gobbi H. , Arteaga C.L. , Jensen R.A. , Simpson J.F. , Dupont W.D. , Olson S.J. , Schuyler P.A. , Plummer W.D. , Page D.L. .
Source: Histopathology, 2000 Feb; 36(2), p. 168-77.
PMID: 10672063
Related Citations

Transforming Growth Factor-beta And Breast Cancer Risk In Women With Mammary Epithelial Hyperplasia
Authors: Gobbi H. , Dupont W.D. , Simpson J.F. , Plummer W.D. , Schuyler P.A. , Olson S.J. , Arteaga C.L. , Page D.L. .
Source: Journal Of The National Cancer Institute, 1999-12-15 00:00:00.0; 91(24), p. 2096-101.
PMID: 10601380
Related Citations

Estrogen Replacement Therapy In Women With A History Of Proliferative Breast Disease
Authors: Dupont W.D. , Page D.L. , Parl F.F. , Plummer W.D. , Schuyler P.A. , Kasami M. , Jensen R.A. .
Source: Cancer, 1999-03-15 00:00:00.0; 85(6), p. 1277-83.
PMID: 10189132
Related Citations

Power And Sample Size Calculations For Studies Involving Linear Regression
Authors: Dupont W.D. , Plummer W.D. .
Source: Controlled Clinical Trials, 1998 Dec; 19(6), p. 589-601.
PMID: 9875838
Related Citations

Association Of Cytochrome P450 1b1 (cyp1b1) Polymorphism With Steroid Receptor Status In Breast Cancer
Authors: Bailey L.R. , Roodi N. , Dupont W.D. , Parl F.F. .
Source: Cancer Research, 1998-11-15 00:00:00.0; 58(22), p. 5038-41.
PMID: 9823305
Related Citations

Monoclonality In Fibroadenomas With Complex Histology And Phyllodal Features
Authors: Kasami M. , Vnencak-Jones C.L. , Manning S. , Dupont W.D. , Jensen R.A. , Page D.L. .
Source: Breast Cancer Research And Treatment, 1998 Jul; 50(2), p. 185-91.
PMID: 9822223
Related Citations

Breast Cancer And Cypia1, Gstm1, And Gstt1 Polymorphisms: Evidence Of A Lack Of Association In Caucasians And African Americans
Authors: Bailey L.R. , Roodi N. , Verrier C.S. , Yee C.J. , Dupont W.D. , Parl F.F. .
Source: Cancer Research, 1998-01-01 00:00:00.0; 58(1), p. 65-70.
PMID: 9426059
Related Citations

Brca2 Hereditary Breast Cancer Pathophenotype
Authors: Marcus J.N. , Watson P. , Page D.L. , Narod S.A. , Tonin P. , Lenoir G.M. , Serova O. , Lynch H.T. .
Source: Breast Cancer Research And Treatment, 1997 Jul; 44(3), p. 275-7.
PMID: 9266108
Related Citations

Loss Of Heterozygosity And Microsatellite Instability In Breast Hyperplasia. No Obligate Correlation Of These Genetic Alterations With Subsequent Malignancy
Authors: Kasami M. , Vnencak-Jones C.L. , Manning S. , Dupont W.D. , Page D.L. .
Source: The American Journal Of Pathology, 1997 Jun; 150(6), p. 1925-32.
PMID: 9176386
Related Citations

Expression Of Most Matrix Metalloproteinase Family Members In Breast Cancer Represents A Tumor-induced Host Response
Authors: Heppner K.J. , Matrisian L.M. , Jensen R.A. , Rodgers W.H. .
Source: The American Journal Of Pathology, 1996 Jul; 149(1), p. 273-82.
PMID: 8686751
Related Citations

Understanding The Relationship Between Relative And Absolute Risk
Authors: Dupont W.D. , Plummer W.D. .
Source: Cancer, 1996-06-01 00:00:00.0; 77(11), p. 2193-9.
PMID: 8635083
Related Citations

Hereditary Breast Cancer: Pathobiology, Prognosis, And Brca1 And Brca2 Gene Linkage
Authors: Marcus J.N. , Watson P. , Page D.L. , Narod S.A. , Lenoir G.M. , Tonin P. , Linder-Stephenson L. , Salerno G. , Conway T.A. , Lynch H.T. .
Source: Cancer, 1996-02-15 00:00:00.0; 77(4), p. 697-709.
PMID: 8616762
Related Citations

Papillary Apocrine Change Of The Breast: Associations With Atypical Hyperplasia And Risk Of Breast Cancer
Authors: Page D.L. , Dupont W.D. , Jensen R.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 1996 Jan; 5(1), p. 29-32.
PMID: 8770463
Related Citations

Continued Local Recurrence Of Carcinoma 15-25 Years After A Diagnosis Of Low Grade Ductal Carcinoma In Situ Of The Breast Treated Only By Biopsy
Authors: Page D.L. , Dupont W.D. , Rogers L.W. , Jensen R.A. , Schuyler P.A. .
Source: Cancer, 1995-10-01 00:00:00.0; 76(7), p. 1197-200.
PMID: 8630897
Related Citations

Evidence Of Efficacy Of Mammographic Screening For Women In Their Forties
Authors: Dupont W.D. .
Source: Cancer, 1994-08-15 00:00:00.0; 74(4), p. 1204-6.
PMID: 8055438
Related Citations

Long-term Risk Of Breast Cancer In Women With Fibroadenoma
Authors: Dupont W.D. , Page D.L. , Parl F.F. , Vnencak-Jones C.L. , Plummer W.D. , Rados M.S. , Schuyler P.A. .
Source: The New England Journal Of Medicine, 1994-07-07 00:00:00.0; 331(1), p. 10-5.
PMID: 8202095
Related Citations

P53 Mutations Are Confined To The Comedo Type Ductal Carcinoma In Situ Of The Breast. Immunohistochemical And Sequencing Data
Authors: O'Malley F.P. , Vnencak-Jones C.L. , Dupont W.D. , Parl F. , Manning S. , Page D.L. .
Source: Laboratory Investigation; A Journal Of Technical Methods And Pathology, 1994 Jul; 71(1), p. 67-72.
PMID: 8041120
Related Citations

P53 Gene Mutations And Steroid Receptor Status In Breast Cancer. Clinicopathologic Correlations And Prognostic Assessment
Authors: Caleffi M. , Teague M.W. , Jensen R.A. , Vnencak-Jones C.L. , Dupont W.D. , Parl F.F. .
Source: Cancer, 1994-04-15 00:00:00.0; 73(8), p. 2147-56.
PMID: 8156519
Related Citations

Ductal Carcinoma In Situ Of The Breast With Apocrine Cytology: Definition Of A Borderline Category
Authors: O'Malley F.P. , Page D.L. , Nelson E.H. , Dupont W.D. .
Source: Human Pathology, 1994 Feb; 25(2), p. 164-8.
PMID: 8119716
Related Citations

Ductal Carcinoma In Situ Of The Breast. Heterogeneity Of Individual Lesions
Authors: Lennington W.J. , Jensen R.A. , Dalton L.W. , Page D.L. .
Source: Cancer, 1994-01-01 00:00:00.0; 73(1), p. 118-24.
PMID: 8275415
Related Citations

Anatomic Indicators (histologic And Cytologic) Of Increased Breast Cancer Risk
Authors: Page D.L. , Dupont W.D. .
Source: Breast Cancer Research And Treatment, 1993 Nov; 28(2), p. 157-66.
PMID: 8173068
Related Citations

Breast Cancer Risk Associated With Proliferative Breast Disease And Atypical Hyperplasia
Authors: Dupont W.D. , Parl F.F. , Hartmann W.H. , Brinton L.A. , Winfield A.C. , Worrell J.A. , Schuyler P.A. , Plummer W.D. .
Source: Cancer, 1993-02-15 00:00:00.0; 71(4), p. 1258-65.
PMID: 8435803
Related Citations

Menopausal Estrogen Replacement Therapy And Breast Cancer
Authors: Dupont W.D. , Page D.L. .
Source: Archives Of Internal Medicine, 1991 Jan; 151(1), p. 67-72.
PMID: 1824675
Related Citations