Grant Number:	5U01CA182915-05 Interpret this number
Primary Investigator:	Meza, Rafael
Organization:	University Of Michigan At Ann Arbor
Project Title:	From Mechanism to Population: Modeling HPV-Related Oropharyngeal Carcinogenesis
Fiscal Year:	2018

DESCRIPTION (provided by applicant): While cervical and other genital cancers are primarily caused by Human Papilloma Virus (HPV) infections, recent studies have demonstrated that HPV is also associated with head and neck (HN) cancers. The prevalence of oral HPV infection among men and women aged 14 to 69 years in the US is about 7%, however, 90% of University of Michigan (UM) oropharyngeal squamous cancer (OPSC) patients carry high-risk HPV. Indeed, the incidence of HPV- associated OPSCs is increasing and OPSC has become the most common HPV-related cancer in the US. HPV has been shown to disrupt several key cancer pathways in oropharyngeal squamous cell lines, including p53 and Rb, but many open questions remain regarding oral HPV transmission epidemiology, infection and persistence, the mechanisms of HPV HN carcinogenesis, and the connection between the ongoing oral HPV epidemic and the rising OPSC incidence. The overarching goal of this proposal is to understand the mechanistic effects of HPV infection on the regulatory pathways of oropharyngeal carcinogenesis, and how these effects in turn shape the observed age-specific incidence and mortality of OPSCs. This problem is inherently multi-scale, as population level HPV transmission drives dynamic, ongoing changes to intracellular cancer regulatory pathways, which in turn drives population-level trends in cancer incidence and mortality. Thus, understanding the rising incidence in OPSC necessitates tying together both the population level processes of infectious disease and the population-level cancer incidence through the mechanistic interactions between HPV and carcinogenesis. Toward this goal, we will develop systems biology models of the main proliferation regulatory networks affected by HPV, and assess the consequences of HPV infection, integration and alternate transcripts on the dynamics of HPV-positive tumor cell proliferation. We will integrate these mechanistic infection and cancer models into multistage models of carcinogenesis to gauge the impacts of HPV infection on the population-level age-specific incidence and mortality of OPSC. We will use these integrated multiscale cancer models in combination with population-level oral HPV transmission models to predict the effects of current HPV prevalence trends on future rates of OPSCs and the potential impact of vaccination and other prevention strategies. Our systems models will be based on multiscale inference using mechanistic infection and cancer data.




Understanding the mechanisms of HPV-related carcinogenesis: Implications for cell cycle dynamics.
Authors: Sund D.T. , Brouwer A.F. , Walline H.M. , Carey T.E. , Meza R. , Jackson T. , Eisenberg M.C. .
Source: Journal Of Theoretical Biology, 2022-11-07 00:00:00.0; 551-552, p. 111235.
EPub date: 2022-08-13 00:00:00.0.
PMID: 35973606
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Oral human papillomavirus prevalence, persistence, and risk-factors in HIV-positive and HIV-negative adults.
Authors: Riddell J. , Brouwer A.F. , Walline H.M. , Campredon L.P. , Meza R. , Eisenberg M.C. , Andrus E.C. , Delinger R.L. , Yost M.L. , McCloskey J.K. , et al. .
Source: Tumour Virus Research, 2022 06; 13, p. 200237.
EPub date: 2022-04-20 00:00:00.0.
PMID: 35460939
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Incidence and clearance of oral and cervicogenital HPV infection: longitudinal analysis of the MHOC cohort study.
Authors: Brouwer A.F. , Campredon L.P. , Walline H.M. , Marinelli B.M. , Goudsmit C.M. , Thomas T.B. , Delinger R.L. , Lau Y.K. , Andrus E.C. , Nair T. , et al. .
Source: Bmj Open, 2022-01-03 00:00:00.0; 12(1), p. e056502.
EPub date: 2022-01-03 00:00:00.0.
PMID: 34980629
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Prevalence and determinants of oral and cervicogenital HPV infection: Baseline analysis of the Michigan HPV and Oropharyngeal Cancer (MHOC) cohort study.
Authors: Brouwer A.F. , Campredon L.P. , Walline H.M. , Marinelli B.M. , Goudsmit C.M. , Thomas T.B. , Delinger R.L. , Lau Y.K. , Andrus E.C. , Yost M.L. , et al. .
Source: Plos One, 2022; 17(5), p. e0268104.
EPub date: 2022-05-16 00:00:00.0.
PMID: 35576195
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Characteristics of head and neck squamous cell carcinoma cell Lines reflect human tumor biology independent of primary etiologies and HPV status.
Authors: Nair T.S. , Thomas T.B. , Yang L. , Kakaraparthi B.N. , Morris A.C. , Clark A.M. , Campredon L.P. , Brouwer A.F. , Eisenberg M.C. , Meza R. , et al. .
Source: Translational Oncology, 2020 Oct; 13(10), p. 100808.
EPub date: 2020-06-20 00:00:00.0.
PMID: 32574978
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Time-varying survival effects for squamous cell carcinomas at oropharyngeal and nonoropharyngeal head and neck sites in the United States, 1973-2015.
Authors: Brouwer A.F. , He K. , Chinn S.B. , Mondul A.M. , Chapman C.H. , Ryser M.D. , Banerjee M. , Eisenberg M.C. , Meza R. , Taylor J.M.G. .
Source: Cancer, 2020-09-05 00:00:00.0; , .
EPub date: 2020-09-05 00:00:00.0.
PMID: 32888317
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HPV vaccination has not increased sexual activity or accelerated sexual debut in a college-aged cohort of men and women.
Authors: Brouwer A.F. , Delinger R.L. , Eisenberg M.C. , Campredon L.P. , Walline H.M. , Carey T.E. , Meza R. .
Source: Bmc Public Health, 2019-06-25 00:00:00.0; 19(1), p. 821.
EPub date: 2019-06-25 00:00:00.0.
PMID: 31238911
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Multisite HPV infections in the United States (NHANES 2003-2014): An overview and synthesis.
Authors: Brouwer A.F. , Eisenberg M.C. , Carey T.E. , Meza R. .
Source: Preventive Medicine, 2019 Jun; 123, p. 288-298.
EPub date: 2019-04-05 00:00:00.0.
PMID: 30959071
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Integrating measures of viral prevalence and seroprevalence: a mechanistic modelling approach to explaining cohort patterns of human papillomavirus in women in the USA.
Authors: Brouwer A.F. , Meza R. , Eisenberg M.C. .
Source: Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences, 2019-05-27 00:00:00.0; 374(1773), p. 20180297.
PMID: 30955488
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Identification of the Fraction of Indolent Tumors and Associated Overdiagnosis in Breast Cancer Screening Trials.
Authors: Ryser M.D. , Gulati R. , Eisenberg M.C. , Shen Y. , Hwang E.S. , Etzioni R.B. .
Source: American Journal Of Epidemiology, 2018-10-16 00:00:00.0; , .
EPub date: 2018-10-16 00:00:00.0.
PMID: 30325415
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Dynamics and Determinants of HPV Infection: The Michigan HPV and Oropharyngeal Cancer (M-HOC) Study.
Authors: Eisenberg M.C. , Campredon L.P. , Brouwer A.F. , Walline H.M. , Marinelli B.M. , Lau Y.K. , Thomas T.B. , Delinger R.L. , Sullivan T.S. , Yost M.L. , et al. .
Source: Bmj Open, 2018-10-02 00:00:00.0; 8(10), p. e021618.
EPub date: 2018-10-02 00:00:00.0.
PMID: 30282679
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DNA Concentration from self samples for HPV testing.
Authors: Meza R. , Lau Y.K. , Thomas T.B. , Carey T.E. , Walline H.M. , Eisenberg M.C. .
Source: International Journal Of Cancer, 2018-07-06 00:00:00.0; , .
EPub date: 2018-07-06 00:00:00.0.
PMID: 29978468
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Case Studies of Gastric, Lung, and Oral Cancer Connect Etiologic Agent Prevalence to Cancer Incidence.
Authors: Brouwer A.F. , Eisenberg M.C. , Meza R. .
Source: Cancer Research, 2018-06-15 00:00:00.0; 78(12), p. 3386-3396.
PMID: 29907681
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A confidence building exercise in data and identifiability: Modeling cancer chemotherapy as a case study.
Authors: Eisenberg M.C. , Jain H.V. .
Source: Journal Of Theoretical Biology, 2017-10-27 00:00:00.0; 431, p. 63-78.
EPub date: 2017-07-19 00:00:00.0.
PMID: 28733187
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Acceptability of Human Papillomavirus Self-Sampling for Cervical Cancer Screening in an Indigenous Community in Guatemala.
Authors: Gottschlich A. , Rivera-Andrade A. , Grajeda E. , Alvarez C. , Mendoza Montano C. , Meza R. .
Source: Journal Of Global Oncology, 2017 Oct; 3(5), p. 444-454.
EPub date: 2017-01-18 00:00:00.0.
PMID: 29094082
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Parameter estimation for multistage clonal expansion models from cancer incidence data: A practical identifiability analysis.
Authors: Brouwer A.F. , Meza R. , Eisenberg M.C. .
Source: Plos Computational Biology, 2017 Mar; 13(3), p. e1005431.
EPub date: 2017-03-13 00:00:00.0.
PMID: 28288156
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A Systematic Approach To Determining The Identifiability Of Multistage Carcinogenesis Models
Authors: Brouwer A.F. , Meza R. , Eisenberg M.C. .
Source: Risk Analysis : An Official Publication Of The Society For Risk Analysis, 2016-09-09 00:00:00.0; , .
PMID: 27612302
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Age Effects and Temporal Trends in HPV-Related and HPV-Unrelated Oral Cancer in the United States: A Multistage Carcinogenesis Modeling Analysis.
Authors: Brouwer A.F. , Eisenberg M.C. , Meza R. .
Source: Plos One, 2016; 11(3), p. e0151098.
PMID: 26963717
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Trends in HPV cervical and seroprevalence and associations between oral and genital infection and serum antibodies in NHANES 2003-2012.
Authors: Brouwer A.F. , Eisenberg M.C. , Carey T.E. , Meza R. .
Source: Bmc Infectious Diseases, 2015-12-21 00:00:00.0; 15, p. 575.
EPub date: 2015-12-21 00:00:00.0.
PMID: 26689203
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Transmission heterogeneity and autoinoculation in a multisite infection model of HPV.
Authors: Brouwer A.F. , Meza R. , Eisenberg M.C. .
Source: Mathematical Biosciences, 2015 Dec; 270(Pt A), p. 115-25.
PMID: 26518265
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