There is growing evidence that genes involved with innate immunity and inflammation may impact the risk of prostate cancer, as well as progression of the disease. During the initial funding period of this project we have successfully undertaken a number of complementary studies to investigate some of these candidate genes. Our preliminary results suggest that prostate cancer may be affected by variants in genes involved in the innate immune response and inflammation pathway (i.e., in RNASEL, OAS1, TNF-a, and LTA). We propose building on these findings by comprehensively evaluating the impact of candidate genes involved in this pathway on prostate cancer development and progression. Specifically, we first aim to evaluate the association between prostate cancer and single nucleotide polymorphisms and haplotypes in the following 23 candidate genes: Macrophage Scavenger Receptor 1, Toll-like Receptors 1, 2, 4, 5, 6, and 10, Ribonuclease L.,2',5'Oligoadenylate Sythetase 1 and 2, Interleukin 8, 1 Beta, and 1RN, Macrophage Migration Inhibitory Factor, Tumor Necrosis Factor Alpha, Lymphotoxin Alpha, Macrophage-lnhibitory-Cytokine-1, Cyclooxygenase-2, and five genes in the Nuclear Factor kappa- Beta Pathway. This study will use an existing population recruited during the initial funding period of this grant (N=1,454; 727 cases, 727 matched controls). Cases are men diagnosed with more clinically relevant disease (i.e., Gleason score >. 7, tumor-node-metastasis (TNM) stage > T2c, or prostate-specific antigen (PSA) >10), making this population ideally suited for studying both risk of prostate cancer and disease progression. Therefore, our second aim-is to collect prospective information on the course of the case's disease (e.g., post-treatment PSA levels), and then evaluate the relationship between these candidate genes and prostate cancer progression. Studying the same genes in these two aims will allow us to distinguish whether they are involved in prostate cancer risk and/or progression.
Our final aim i s to synthesize information on the candidate genes studied here by investigating their joint and interactive effects on prostate cancer development and progression with a novel hierarchical model. Determining the impact of candidate genes involved with the innate immunity and inflammation pathway on prostate cancer development and progression may have a significant impact on the public's health. In particular, the knowledge from this study may give important insights into the underlying mechanism of disease, provide a valuable screening tool for non-diseased men, and help guide treatment plans among men diagnosed with prostate cancer. ? ? ? ?
|Cario, Clinton L; Witte, John S (2018) Orchid: a novel management, annotation and machine learning framework for analyzing cancer mutations. Bioinformatics 34:936-942|
|Majumdar, Arunabha; Haldar, Tanushree; Bhattacharya, Sourabh et al. (2018) An efficient Bayesian meta-analysis approach for studying cross-phenotype genetic associations. PLoS Genet 14:e1007139|
|Wu, Yi-Hsuan; Graff, Rebecca E; Passarelli, Michael N et al. (2018) Identification of Pleiotropic Cancer Susceptibility Variants from Genome-Wide Association Studies Reveals Functional Characteristics. Cancer Epidemiol Biomarkers Prev 27:75-85|
|Gauderman, W James; Mukherjee, Bhramar; Aschard, Hugues et al. (2017) Update on the State of the Science for Analytical Methods for Gene-Environment Interactions. Am J Epidemiol 186:762-770|
|Hoffmann, Thomas J; Passarelli, Michael N; Graff, Rebecca E et al. (2017) Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer. Nat Commun 8:14248|
|Ng, Maggie C Y; Graff, Mariaelisa; Lu, Yingchang et al. (2017) Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium. PLoS Genet 13:e1006719|
|Hoffman, Joshua D; Graff, Rebecca E; Emami, Nima C et al. (2017) Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. PLoS Genet 13:e1006690|
|Emami, Nima C; Leong, Lancelote; Wan, Eunice et al. (2017) Tissue Sources for Accurate Measurement of Germline DNA Genotypes in Prostate Cancer Patients Treated With Radical Prostatectomy. Prostate 77:425-434|
|Graff, Rebecca E; Möller, Sören; Passarelli, Michael N et al. (2017) Familial Risk and Heritability of Colorectal Cancer in the Nordic Twin Study of Cancer. Clin Gastroenterol Hepatol 15:1256-1264|
|Conti, David V; Wang, Kan; Sheng, Xin et al. (2017) Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. J Natl Cancer Inst 109:|
Showing the most recent 10 out of 94 publications