|Grant Number:||5R01CA121060-05 Interpret this number|
|Primary Investigator:||Fowke, Jay|
|Project Title:||Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer|
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.
A functional variant in NKX3.1 associated with prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
Authors: Martinez EE, Darke AK, Tangen CM, Goodman PJ, Fowke JH, Klein EA, Abdulkadir SA
Source: Cancer Prev Res (Phila), 2014 Sep;7(9), p. 950-7.
EPub date: 2014 Jun 3.
Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.
Authors: Luo Y, Wong CJ, Kaz AM, Dzieciatkowski S, Carter KT, Morris SM, Wang J, Willis JE, Makar KW, Ulrich CM, Lutterbaugh JD, Shrubsole MJ, Zheng W, Markowitz SD, Grady WM
Source: Gastroenterology, 2014 Aug;147(2), p. 418-29.e8.
EPub date: 2014 Apr 30.
Pleiotropy between genetic markers of obesity and risk of prostate cancer.
Authors: Edwards TL, Giri A, Motley S, Duong W, Fowke JH
Source: Cancer Epidemiol Biomarkers Prev, 2013 Sep;22(9), p. 1538-46.
EPub date: 2013 Jun 27.
Genome-wide association study identifies possible genetic risk factors for colorectal adenomas.
Authors: Edwards TL, Shrubsole MJ, Cai Q, Li G, Dai Q, Rex DK, Ulbright TM, Fu Z, Delahanty RH, Murff HJ, Smalley W, Ness RM, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jul;22(7), p. 1219-26.
EPub date: 2013 May 15.
Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.
Authors: Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, Berndt SI, Bézieau S, Brenner H, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Chen LS, Coetzee GA, Coetzee SG, Conti DV, Curtis KR, Duggan D, Edwards T, Fuchs CS, Gallinger S, Giovannucci EL, Gogarten SM, Gruber SB, Haile RW, Harrison TA, Hayes RB, Henderson BE, Hoffmeister M, Hopper JL, Hudson TJ, Hunter DJ, Jackson RD, Jee SH, Jenkins MA, Jia WH, Kolonel LN, Kooperberg C, Küry S, Lacroix AZ, Laurie CC, Laurie CA, Le Marchand L, Lemire M, Levine D, Lindor NM, Liu Y, Ma J, Makar KW, Matsuo K, Newcomb PA, Potter JD, Prentice RL, Qu C, Rohan T, Rosse SA, Schoen RE, Seminara D, Shrubsole M, Shu XO, Slattery ML, Taverna D, Thibodeau SN, Ulrich CM, White E, Xiang Y, Zanke BW, Zeng YX, Zhang B, Zheng W, Hsu L, Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium
Source: Gastroenterology, 2013 Apr;144(4), p. 799-807.e24.
EPub date: 2012 Dec 22.
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 JH, Motley S, Dai Q, Concepcion R, Barocas DA
Source: Cancer Lett, 2013 Jan 28;328(2), p. 345-52.
EPub date: 2012 Oct 16.
Association between physical activity, lower urinary tract symptoms (LUTS) and prostate volume.
Authors: Fowke JH, Phillips S, Koyama T, Byerly S, Concepcion R, Motley SS, Clark PE
Source: BJU Int, 2013 Jan;111(1), p. 122-8.
EPub date: 2012 Jun 22.
A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma.
Authors: Edwards TL, Shrubsole MJ, Cai Q, Li G, Dai Q, Rex DK, Ulbright TM, Fu Z, Murff HJ, Smalley W, Ness R, Zheng W
Source: Cancer Prev Res (Phila), 2012 Jun;5(6), p. 855-63.
EPub date: 2012 May 2.
Obesity, body composition, and prostate cancer.
Authors: Fowke JH, Motley SS, Concepcion RS, Penson DF, Barocas DA
Source: BMC Cancer, 2012 Jan 18;12, p. 23.
EPub date: 2012 Jan 18.
Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer.
Authors: Dai Q, Motley SS, Smith JA Jr, Concepcion R, Barocas D, Byerly S, Fowke JH
Source: PLoS One, 2011 Apr 25;6(4), p. e18237.
EPub date: 2011 Apr 25.
Oxidative stress measured by urine F2-isoprostane level is associated with prostate cancer.
Authors: Barocas DA, Motley S, Cookson MS, Chang SS, Penson DF, Dai Q, Milne G, Roberts LJ 2nd, Morrow J, Concepcion RS, Smith JA Jr, Fowke JH
Source: J Urol, 2011 Jun;185(6), p. 2102-7.
EPub date: 2011 Apr 15.
The associations between statin use and prostate cancer screening, prostate size, high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer.
Authors: Fowke JH, Motley SS, Barocas DA, Cookson MS, Concepcion R, Byerly S, Smith JA Jr
Source: Cancer Causes Control, 2011 Mar;22(3), p. 417-26.
EPub date: 2010 Dec 19.
PSA and body composition by dual X-ray absorptiometry (DXA) in NHANES.
Authors: Fowke JH, Matthews CE
Source: Prostate, 2010 Feb 1;70(2), p. 120-5.
Association of nonsteroidal anti-inflammatory drugs, prostate specific antigen and prostate volume.
Authors: Fowke JH, Motley SS, Smith JA Jr, Cookson MS, Concepcion R, Chang SS, Byerly S
Source: J Urol, 2009 May;181(5), p. 2064-70.
EPub date: 2009 Mar 14.