From Mechanism to Population: Modeling HPV-related Oropharyngeal Carcinogenesis

描述（由申请人提供）：虽然宫颈癌和其他生殖器癌症主要由人乳头瘤病毒（HPV）感染引起，但最近的研究表明，HPV也与头颈部（HN）癌症有关。在美国14 - 69岁的男性和女性中，口腔HPV感染的患病率约为7%，然而，90%的密歇根大学（UM）口咽鳞状癌（OPSC）患者携带高危HPV。事实上，HPV相关的OPSC的发病率正在增加，OPSC已成为美国最常见的HPV相关癌症。HPV已被证明可以破坏口咽鳞状细胞系的几个关键癌症通路，包括p53和Rb，但关于口腔HPV传播流行病学，感染和持久性，HPV HN致癌机制以及持续的口腔HPV流行与OPSC发病率上升之间的联系仍有许多悬而未决的问题。本提案的总体目标是了解HPV感染对口咽癌发生调节途径的机制影响，以及这些影响如何反过来影响观察到的年龄特异性opsc发病率和死亡率。这个问题本质上是多尺度的，因为人群水平的HPV传播驱动了细胞内癌症调节途径的动态、持续变化，这反过来又驱动了癌症发病率和死亡率的人群水平趋势。因此，了解OPSC发病率的上升需要通过HPV之间的机制相互作用将传染病的人口水平过程和人口水平癌症发病率联系起来

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.