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Grant Details

Grant Number: 5R01CA121060-05 Interpret this number
Primary Investigator: Fowke, Jay
Organization: Vanderbilt University
Project Title: Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer
Fiscal Year: 2011
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Abstract

Prostate cells respond to estrogens, insulin, and other factors largely regulated in men by adipose mass. Several recent studies report obesity associated with high-grade prostate cancer, progression, and mortality, however the association with low-grade cancer common in the PSA era remains unclear. Challenges include measuring fat deposition patterns, excluding latent cancer from control groups, and controlling for several potential biases associated the effects of obesity on prostate cancer detection. Our study aims to address these challenges and determine the relationship between total adiposity (e.g., BMI, estrogens) and visceral adiposity (e.g., waist circumference, WHR, insulin) across high-grade cancer, low-grade cancer, and prostatic intraepithelial neoplasia (PIN). Preliminary analyses (R21 CA98348, n=304 cancer, 120 PIN, 424 controls) found WHR significantly associated with PIN (WHR>1.03: OR = 4.75 95% Cl (1.71, 13.2), ptrend<0.01, adjusted for PSA, BMI, prostate volume, age race, ORE result, # cores). Also, BMI>35 was associated with high-grade (Gleasons7) cancer (ORadj=3.49 (0.84, 14.4), ptrend = 0.05). Thus, visceral adiposity and the related metabolic syndrome may impact early prostate carcinogenesis, while an estrogen- rich environment associated with greater BMI may accelerate progression to high-grade/clinically relevant disease. Using our established multi-centered rapid-recruitment protocol, we will recruit an additional 1,106 prostate cancer cases (42% Gleason &7), 435 PIN cases, and 1,544 controls without cancer or PIN at prostate biopsy. Data and specimens (questionnaires for diet, physical activity, and other risk factors; body measures for BMI, WHR, sitting height, and % body fat (BIA); blood for DNA and hormone levels) are collected before diagnosis. Genes representing pathways linking total adiposity (e.g., Lep, LepR, CYP19, ER,AR, SHBG) or visceral adiposity (Res, Adip, AdipR1/2, INS, IRS1/2, IGF1, IGFBP3, PPARy2) to PIN or cancer will be investigated using multivariable logistic regression. Also, we will investigate blood markers of adiposity and PIN in an individually matched analysis (total adiposity: leptin, E2/T ratio, SHBG; visceral adiposity: HbA1c, adiponectin, resistin). Obesity is epidemic in the U.S., and prostate cancer is a leading cause of cancer-related death. Ongoing chemoprevention studies target PIN, and our results may identify new obesity-based prevention approaches or improve the prognosis of prostate cancer patients.

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Publications

Blood and dietary magnesium levels are not linked with lower prostate cancer risk in black or white men.
Authors: Fowke J.H. , Koyama T. , Dai Q. , Zheng S.L. , Xu J. , Howard L.E. , Freedland S.J. .
Source: Cancer letters, 2019-05-01; 449, p. 99-105.
EPub date: 2019-02-15.
PMID: 30776477
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Statin use linked with a decrease in the conversion from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer.
Authors: Fowke J.H. , Motley S.S. .
Source: Carcinogenesis, 2018-05-28; 39(6), p. 819-825.
PMID: 29617729
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Molecular correlates in urine for the obesity and prostatic inflammation of BPH/LUTS patients.
Authors: Tyagi P. , Motley S.S. , Koyama T. , Kashyap M. , Gingrich J. , Yoshimura N. , Fowke J.H. .
Source: The Prostate, 2018 Jan; 78(1), p. 17-24.
EPub date: 2017-10-27.
PMID: 29080225
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Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage.
Authors: Velez Edwards D.R. , Edwards T.L. , Bray M.J. , Torstenson E. , Jones S. , Shrubsole M.J. , Muff H.J. , Hartmann K.E. .
Source: Scientific reports, 2017-08-29; 7(1), p. 9874.
EPub date: 2017-08-29.
PMID: 28852049
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Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two-phase study.
Authors: Zhao J. , Zhu X. , Shrubsole M.J. , Ness R.M. , Hibler E.A. , Cai Q. , Long J. , Chen Z. , Jiang M. , Kabagambe E.K. , et al. .
Source: Molecular carcinogenesis, 2017 10; 56(10), p. 2258-2266.
EPub date: 2017-06-15.
PMID: 28544176
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Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.
Authors: Sun P. , Zhu X. , Shrubsole M.J. , Ness R.M. , Hibler E.A. , Cai Q. , Long J. , Chen Z. , Li G. , Hou L. , et al. .
Source: The Journal of nutritional biochemistry, 2017 09; 47, p. 35-40.
EPub date: 2017-05-05.
PMID: 28501704
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Calcium/magnesium intake ratio, but not magnesium intake, interacts with genetic polymorphism in relation to colorectal neoplasia in a two-phase study.
Authors: Zhu X. , Shrubsole M.J. , Ness R.M. , Hibler E.A. , Cai Q. , Long J. , Chen Z. , Li G. , Jiang M. , Hou L. , et al. .
Source: Molecular carcinogenesis, 2016 10; 55(10), p. 1449-57.
EPub date: 2015-08-31.
PMID: 26333203
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Genetic Determinants of Metabolism and Benign Prostate Enlargement: Associations with Prostate Volume.
Authors: Giri A. , Edwards T.L. , Motley S.S. , Byerly S.H. , Fowke J.H. .
Source: PloS one, 2015; 10(7), p. e0132028.
EPub date: 2015-07-09.
PMID: 26158673
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Calcium intake and ion transporter genetic polymorphisms interact in human colorectal neoplasia risk in a 2-phase study.
Authors: Zhu X. , Liang J. , Shrubsole M.J. , Ness R.M. , Cai Q. , Long J. , Chen Z. , Li G. , Wiese D. , Zhang B. , et al. .
Source: The Journal of nutrition, 2014 Nov; 144(11), p. 1734-41.
EPub date: 2014-08-27.
PMID: 25165391
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A functional variant in NKX3.1 associated with prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
Authors: Martinez E.E. , Darke A.K. , Tangen C.M. , Goodman P.J. , Fowke J.H. , Klein E.A. , Abdulkadir S.A. .
Source: Cancer prevention research (Philadelphia, Pa.), 2014 Sep; 7(9), p. 950-7.
EPub date: 2014-06-03.
PMID: 24894197
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Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.
Authors: Luo Y. , Wong C.J. , Kaz A.M. , Dzieciatkowski S. , Carter K.T. , Morris S.M. , Wang J. , Willis J.E. , Makar K.W. , Ulrich C.M. , et al. .
Source: Gastroenterology, 2014 Aug; 147(2), p. 418-29.e8.
EPub date: 2014-04-30.
PMID: 24793120
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Pleiotropy between genetic markers of obesity and risk of prostate cancer.
Authors: Edwards T.L. , Giri A. , Motley S. , Duong W. , Fowke J.H. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2013 Sep; 22(9), p. 1538-46.
EPub date: 2013-06-27.
PMID: 23810916
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Genome-wide association study identifies possible genetic risk factors for colorectal adenomas.
Authors: Edwards T.L. , Shrubsole M.J. , Cai Q. , Li G. , Dai Q. , Rex D.K. , Ulbright T.M. , Fu Z. , Delahanty R.H. , Murff H.J. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2013 Jul; 22(7), p. 1219-26.
EPub date: 2013-05-15.
PMID: 23677573
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Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.
Authors: Peters U. , Jiao S. , Schumacher F.R. , Hutter C.M. , Aragaki A.K. , Baron J.A. , Berndt S.I. , B├ęzieau S. , Brenner H. , Butterbach K. , et al. .
Source: Gastroenterology, 2013 Apr; 144(4), p. 799-807.e24.
EPub date: 2012-12-22.
PMID: 23266556
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Association between biomarkers of obesity and risk of high-grade prostatic intraepithelial neoplasia and prostate cancer--evidence of effect modification by prostate size.
Authors: Fowke J.H. , Motley S. , Dai Q. , Concepcion R. , Barocas D.A. .
Source: Cancer letters, 2013-01-28; 328(2), p. 345-52.
EPub date: 2012-10-16.
PMID: 23079532
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Association between physical activity, lower urinary tract symptoms (LUTS) and prostate volume.
Authors: Fowke J.H. , Phillips S. , Koyama T. , Byerly S. , Concepcion R. , Motley S.S. , Clark P.E. .
Source: BJU international, 2013 Jan; 111(1), p. 122-8.
EPub date: 2012-06-22.
PMID: 22726636
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A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma.
Authors: Edwards T.L. , Shrubsole M.J. , Cai Q. , Li G. , Dai Q. , Rex D.K. , Ulbright T.M. , Fu Z. , Murff H.J. , Smalley W. , et al. .
Source: Cancer prevention research (Philadelphia, Pa.), 2012 Jun; 5(6), p. 855-63.
EPub date: 2012-05-02.
PMID: 22551900
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Obesity, body composition, and prostate cancer.
Authors: Fowke J.H. , Motley S.S. , Concepcion R.S. , Penson D.F. , Barocas D.A. .
Source: BMC cancer, 2012-01-18; 12, p. 23.
EPub date: 2012-01-18.
PMID: 22257467
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Oxidative stress measured by urine F2-isoprostane level is associated with prostate cancer.
Authors: Barocas D.A. , Motley S. , Cookson M.S. , Chang S.S. , Penson D.F. , Dai Q. , Milne G. , Roberts L.J. , Morrow J. , Concepcion R.S. , et al. .
Source: The Journal of urology, 2011 Jun; 185(6), p. 2102-7.
EPub date: 2011-04-15.
PMID: 21496850
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Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer.
Authors: Dai Q. , Motley S.S. , Smith J.A. , Concepcion R. , Barocas D. , Byerly S. , Fowke J.H. .
Source: PloS one, 2011-04-25; 6(4), p. e18237.
EPub date: 2011-04-25.
PMID: 21541018
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The associations between statin use and prostate cancer screening, prostate size, high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer.
Authors: Fowke J.H. , Motley S.S. , Barocas D.A. , Cookson M.S. , Concepcion R. , Byerly S. , Smith J.A. .
Source: Cancer causes & control : CCC, 2011 Mar; 22(3), p. 417-26.
EPub date: 2010-12-19.
PMID: 21170754
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PSA and body composition by dual X-ray absorptiometry (DXA) in NHANES.
Authors: Fowke J.H. , Matthews C.E. .
Source: The Prostate, 2010-02-01; 70(2), p. 120-5.
PMID: 19739130
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Association of nonsteroidal anti-inflammatory drugs, prostate specific antigen and prostate volume.
Authors: Fowke J.H. , Motley S.S. , Smith J.A. , Cookson M.S. , Concepcion R. , Chang S.S. , Byerly S. .
Source: The Journal of urology, 2009 May; 181(5), p. 2064-70.
EPub date: 2009-03-14.
PMID: 19286210
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Re: North American white mitochondrial haplogroups in prostate and renal cancer.
Authors: Canter J.A. , Kallianpur A.R. , Fowke J.H. .
Source: The Journal of urology, 2006 Nov; 176(5), p. 2308-9; author reply 2309.
PMID: 17070319
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