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Grant Details

Grant Number: 1U19CA214253-01A1 Interpret this number
Primary Investigator: Haiman, Christopher
Organization: University Of Southern California
Project Title: Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Stress (RESPOND)
Fiscal Year: 2018


Abstract

Abstract – Program Project Overview African American (AA) men have a >60% higher incidence and are more likely to be diagnosed with aggressive PCa than white men. Reasons for the greater burden of aggressive disease in AA men are unknown, but are likely to include a multitude of factors including social factors such as lifetime stress, inherited susceptibility, and tumor-related features such as somatic alterations and local inflammation in the microenvironment. The overarching goal of this Program Project is to uncover the social and biological factors that are related to PCa aggressiveness in AA men. To accomplish this objective, we will establish a large, national, population-based cohort study, RESPOND, (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Social Stress) of 10,000 AA men with incident PCa identified through nine SEER and NPCR U.S. cancer registries from states that include 38% of all AA PCa cases in the U.S.. The cohort will provide comprehensive information on multilevel stressors over the lifecourse such as discrimination, early-life adversity, and neighborhood disorder, including geospatial neighborhood data over time and degree of perceived stress; 2) lifestyle factors and health behaviors; 3) disease-specific factors including PSA screening history and treatment choice; 4) germline DNA to study genetic susceptibility, and 5) tumor block samples for characterization of somatic variation and immune profiling of the tumor microenvironment. No previous study has attempted to obtain information across these domains in a single large sample in order to understand the relative contribution of each and relationships between molecular and non-genetic components. In order to address these goals, we have assembled a multi-disciplinary team of scientists and clinicians with established track records in PCa research. Leveraging the RESPOND resource and investigator expertise, we have designed a Program Project composed of four Projects that are supported by four Cores which are all focused on the central theme of identifying social and biological factors related to PCa disease aggressiveness in AA men. These Projects include: the investigation of multilevel social stressors across the lifecourse in relationship with aggressive PCa (Project 1); genome-wide discovery efforts of germline susceptibility loci for aggressive PCa and examination of the relationship between germline and somatic variation (Project 2); the identification of underlying somatic alterations in PCa tumors and biological pathways that are related to aggressive disease (Project 3); and, a detailed assessment of inflammation in the tumor microenvironment as it relates to PCa aggressiveness in AA men (Project 4). Each of the four Projects address a distinct research domain, however, when studied together, create scientific synergy and a far more comprehensive picture of the major factors that contribute to aggressive PCa in AA men. The information we will discover is likely to have immediate clinical implications in the areas of improved patient stratification and personalized medicine. Hence, this study has broad reaching significance and addresses numerous challenges in the clinical management of PCa in AA men.



Publications

Hierarchical joint analysis of marginal summary statistics-Part I: Multipopulation fine mapping and credible set construction.
Authors: Shen J. , Jiang L. , Wang K. , Wang A. , Chen F. , Newcombe P.J. , Haiman C.A. , Conti D.V. .
Source: Genetic Epidemiology, 2024 Sep; 48(6), p. 241-257.
EPub date: 2024-04-12 00:00:00.0.
PMID: 38606643
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Integrating Multi-Omics with environmental data for precision health: A novel analytic framework and case study on prenatal mercury induced childhood fatty liver disease.
Authors: Goodrich J.A. , Wang H. , Jia Q. , Stratakis N. , Zhao Y. , Maitre L. , Bustamante M. , Vafeiadi M. , Aung M. , Andrušaitytė S. , et al. .
Source: Environment International, 2024 Aug; 190, p. 108930.
EPub date: 2024-08-03 00:00:00.0.
PMID: 39128376
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Hierarchical joint analysis of marginal summary statistics-Part II: High-dimensional instrumental analysis of omics data.
Authors: Jiang L. , Shen J. , Darst B.F. , Haiman C.A. , Mancuso N. , Conti D.V. .
Source: Genetic Epidemiology, 2024-06-17 00:00:00.0; , .
EPub date: 2024-06-17 00:00:00.0.
PMID: 38887957
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Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry.
Authors: Hughley R.W. , Matejcic M. , Song Z. , Sheng X. , Wan P. , Xia L. , Hart S.N. , Hu C. , Yadav S. , Lubwama A. , et al. .
Source: Cancer Research Communications, 2023-11-28 00:00:00.0; 3(12), p. 2544-50.
EPub date: 2023-11-28 00:00:00.0.
PMID: 38014910
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.
Authors: Wang A. , Shen J. , Rodriguez A.A. , Saunders E.J. , Chen F. , Janivara R. , Darst B.F. , Sheng X. , Xu Y. , Chou A.J. , et al. .
Source: Nature Genetics, 2023-11-09 00:00:00.0; , .
EPub date: 2023-11-09 00:00:00.0.
PMID: 37945903
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Club-like cells in proliferative inflammatory atrophy of the prostate.
Authors: Huang F.W. , Song H. , Weinstein H.N. , Xie J. , Cooperberg M.R. , Hicks J. , Mummert L. , De Marzo A.M. , Sfanos K.S. .
Source: The Journal Of Pathology, 2023-08-07 00:00:00.0; , .
EPub date: 2023-08-07 00:00:00.0.
PMID: 37550827
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Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.
Authors: Darst B.F. , Shen J. , Madduri R.K. , Rodriguez A.A. , Xiao Y. , Sheng X. , Saunders E.J. , Dadaev T. , Brook M.N. , Hoffmann T.J. , et al. .
Source: American Journal Of Human Genetics, 2023-07-06 00:00:00.0; 110(7), p. 1200-1206.
EPub date: 2023-06-12 00:00:00.0.
PMID: 37311464
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Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.
Authors: Darst B.F. , Shen J. , Madduri R.K. , Rodriguez A.A. , Xiao Y. , Sheng X. , Saunders E.J. , Dadaev T. , Brook M.N. , Hoffmann T.J. , et al. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-05-15 00:00:00.0; , .
EPub date: 2023-05-15 00:00:00.0.
PMID: 37292833
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Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.
Authors: Chen F. , Madduri R.K. , Rodriguez A.A. , Darst B.F. , Chou A. , Sheng X. , Wang A. , Shen J. , Saunders E.J. , Rhie S.K. , et al. .
Source: European Urology, 2023-02-27 00:00:00.0; , .
EPub date: 2023-02-27 00:00:00.0.
PMID: 36872133
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Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing.
Authors: Sheng X. , Xia L. , Cahoon J.L. , Conti D.V. , Haiman C.A. , Kachuri L. , Chiang C.W.K. .
Source: Hgg Advances, 2023-01-12 00:00:00.0; 4(1), p. 100159.
EPub date: 2022-11-11 00:00:00.0.
PMID: 36465187
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Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: a meta-analysis within diverse populations.
Authors: Chen F. , Darst B.F. , Madduri R.K. , Rodriguez A.A. , Sheng X. , Rentsch C.T. , Andrews C. , Tang W. , Kibel A.S. , Plym A. , et al. .
Source: Elife, 2022-07-08 00:00:00.0; 11, .
EPub date: 2022-07-08 00:00:00.0.
PMID: 35801699
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Contributions of Social Factors to Disparities in Prostate Cancer Risk Profiles among Black Men and Non-Hispanic White Men with Prostate Cancer in California.
Authors: Press D.J. , Shariff-Marco S. , Lichtensztajn D.Y. , Lauderdale D. , Murphy A.B. , Inamdar P.P. , DeRouen M.C. , Hamilton A.S. , Yang J. , Lin K. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2022 Feb; 31(2), p. 404-412.
EPub date: 2021-11-30 00:00:00.0.
PMID: 34853020
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A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry.
Authors: Darst B.F. , Hughley R. , Pfennig A. , Hazra U. , Fan C. , Wan P. , Sheng X. , Xia L. , Andrews C. , Chen F. , et al. .
Source: European Urology, 2022-01-11 00:00:00.0; , .
EPub date: 2022-01-11 00:00:00.0.
PMID: 35031163
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A Hierarchical Approach Using Marginal Summary Statistics for Multiple Intermediates in a Mendelian Randomization or Transcriptome Analysis.
Authors: Jiang L. , Xu S. , Mancuso N. , Newcombe P.J. , Conti D.V. .
Source: American Journal Of Epidemiology, 2021-06-01 00:00:00.0; 190(6), p. 1148-1158.
PMID: 33404048
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Evaluating the transcriptional fidelity of cancer models.
Authors: Peng D. , Gleyzer R. , Tai W.H. , Kumar P. , Bian Q. , Isaacs B. , da Rocha E.L. , Cai S. , DiNapoli K. , Huang F.W. , et al. .
Source: Genome Medicine, 2021-04-29 00:00:00.0; 13(1), p. 73.
EPub date: 2021-04-29 00:00:00.0.
PMID: 33926541
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Differential mast cell phenotypes in benign versus cancer tissues and prostate cancer oncologic outcomes.
Authors: Hempel Sullivan H. , Maynard J.P. , Heaphy C.M. , Lu J. , De Marzo A.M. , Lotan T.L. , Joshu C.E. , Sfanos K.S. .
Source: The Journal Of Pathology, 2020-12-18 00:00:00.0; , .
EPub date: 2020-12-18 00:00:00.0.
PMID: 33338262
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A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.
Authors: Darst B.F. , Wan P. , Sheng X. , Bensen J.T. , Ingles S.A. , Rybicki B.A. , Nemesure B. , John E.M. , Fowke J.H. , Stevens V.L. , et al. .
Source: European Urology, 2020 Sep; 78(3), p. 316-320.
EPub date: 2020-05-12 00:00:00.0.
PMID: 32409115
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Genomic Profiling of Prostate Cancers from Men with African and European Ancestry.
Authors: Koga Y. , Song H. , Chalmers Z.R. , Newberg J. , Kim E. , Carrot-Zhang J. , Piou D. , Polak P. , Abdulkadir S.A. , Ziv E. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2020-09-01 00:00:00.0; 26(17), p. 4651-4660.
EPub date: 2020-07-10 00:00:00.0.
PMID: 32651179
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A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer.
Authors: Walavalkar K. , Saravanan B. , Singh A.K. , Jayani R.S. , Nair A. , Farooq U. , Islam Z. , Soota D. , Mann R. , Shivaprasad P.V. , et al. .
Source: Nature Communications, 2020-07-17 00:00:00.0; 11(1), p. 3598.
EPub date: 2020-07-17 00:00:00.0.
PMID: 32680982
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Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers.
Authors: Stern J.L. , Hibshman G. , Hu K. , Ferrara S.E. , Costello J.C. , Kim W. , Tamayo P. , Cech T.R. , Huang F.W. .
Source: Molecular Cancer Research : Mcr, 2020 07; 18(7), p. 1050-1062.
EPub date: 2020-04-10 00:00:00.0.
PMID: 32276990
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Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells.
Authors: Song H. , Seddighzadeh B. , Cooperberg M.R. , Huang F.W. .
Source: Biorxiv : The Preprint Server For Biology, 2020-04-25 00:00:00.0; , .
EPub date: 2020-04-25 00:00:00.0.
PMID: 32510524
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