William Aronson

MD

University of California Los Angeles

Clinical Professor

PLCO (Learn more about this study)

PLCO-274

May 8, 2017

Effect of Dietary Omega-3 fatty acids and GPR120 Single Nucleotide Polymorphisms on Prostate Cancer Chemoprevention

Fish oil dietary supplements are among the most popular dietary supplements worldwide and are commonly consumed to lower triglyceride levels. However, evidence for the benefit of fish oil dietary supplements for the prevention and treatment of prostate cancer is less conclusive. In a prospective randomized pre-prostatectomy trial conducted by our group, a low-fat diet with fish oil supplement (LF/FO) intervention decreased proliferation of prostate cancer epithelium as measured by the Ki-67 index, and decreased the Cell Cycle Progression Score1. GPR120 (FFAR4), a g-protein coupled fatty acid receptor, mediates long chain fatty acid signaling, including ω-3 fatty acids from fish2. GPR120 gene expression in prostatectomy tissue from the above-mentioned trial in men consuming fish oil was negatively correlated with Ki-67 immuno-staining, suggesting that higher GPR120 expression may predict greater responsiveness to dietary fish oil. Mouse studies, performed in our laboratory, have demonstrated that feeding a diet containing fish oil delays growth of prostate cancer allografts in immunocompetent mice3. Recent unpublished data from our laboratory demonstrated that the deletion of GPR120 in these mice reversed the anticarcinogenic effect of dietary fish oil. Therefore, host GPR120 status may play a key role in responsiveness to fish oil-based dietary interventions. In human studies, six genetic variants of GPR120 have been identified. A low-frequency GPR120 SNP (Rs116454156) has been associated with obesity, while another more common GPR120 SNP (RS 12415204), with a frequency of up to 25% in the population, is associated with family history of lung cancer and increased risk of lung cancer 4,5. We now propose to use publically available data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to examine the role of dietary omega-3 fatty acids and GPR120 SNPs on the chemoprevention of prostate cancer. We will use data on patient characteristics, disease parameters, and dietary intake deposited in CDAS in combination with GWAS data from PLCO deposited in dbGAP.
Cox-proportional hazards regression models will be used to evaluate predictors for the outcome of time to development of prostate cancer. Initial predictors in the model will be standard prostate cancer risk factors (age, baseline PSA, etc). In the models, we will assess the risk of prostate cancer from dietary omega-3 fatty acids and GPR120 SNPs separately and from their potential interaction effects. A secondary analysis will evaluate the outcome of time to development of low grade and high-grade prostate cancer using the same type of model structure.

References:

1. Aronson WJ, et al. Cancer Prev Res (Phila). Dec 2011;4(12):2062-2071.
2. Oh DY, et al. Cell. Sep 3 2010;142(5):687-698.
3. Kobayashi N, et al. Clin Cancer Res. Aug 1 2006;12(15):4662-4670.
4. Ichimura A, et al. Nature. Mar 15 2012;483(7389):350-354.
5. Poirier JG, et al. Genet Epidemiol. Mar 2015;39(3):197-206.

Based on the mouse and human studies reported in the above summary, we hypothesize that the anticarcinogenic effects of dietary omega-3 fatty acids are mediated, in part, through GPR120 related mechanisms in the host immune system. To determine the impact of GPR120 SNPs on the chemopreventive effects of dietary omega-3 fatty acids from fish we propose the following specific aims:

Specific Aim 1: Determine the effect of dietary intake of omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish on risk of low grade (GG < 3+3), high grade (GG > 4+4), and overall prostate cancer in PLCO. ,

Specific Aim 2: Determine the effect of GPR120 single nucleotide polymorphisms on risk of low grade (GG < 3+3), high grade (GG > 4+4), and overall prostate cancer in PLCO.

Specific Aim 3: Determine if GPR120 single nucleotide polymorphisms in men that participated in the PLCO trial impact on the association between dietary omega-3 fatty acids, and the risk of low grade (GG < 3+3), high grade (GG > 4+4), and overall prostate cancer in PLCO.

Principal Investigator:
William Aronson, M.D., University of California Los Angeles, David Geffen School of Medicine,
Co-Investigators:
Gerald Andriole, M.D., Washington University School of Medicine, St. Louis, MO
Eric Miller, Ph.D., National Cancer Institute
David Elashoff, PhD, University of California Los Angeles, David Geffen School of Medicine,