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.

Public Health Relevance

The incidence of Human Papilloma Virus (HPV)-associated oropharyngeal cancer (OPSC) is increasing, with oropharyngeal cancer recently surpassing cervical cancer as the most common HPV-related cancer in the US, and 90% of University of Michigan (UM) OPSCs containing HPV. However, there remain numerous open questions about the mechanisms by which HPV induces OPSC, and the connection between the ongoing oral HPV epidemic and the rising OPSC trends. We will develop multiscale models of oropharyngeal carcinogenesis and HPV transmission to investigate the biological mechanisms by which HPV causes cancers in the oropharynx and to predict the potential impact of HPV vaccination and other prevention strategies on OPSC rates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA182915-01A1
Application #
8756361
Study Section
Special Emphasis Panel (ZCA1-SRLB-B (M1))
Program Officer
Mariotto, Angela B
Project Start
2014-09-11
Project End
2019-08-31
Budget Start
2014-09-11
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$630,151
Indirect Cost
$221,064
Name
University of Michigan Ann Arbor
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109