Date of Award

January 2015

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Wendell G. Yarbrough

Subject Area(s)

Medicine

Abstract

Background: Oral cavity squamous cell carcinoma (OCSCC) has been reported to have stagnant survival rates over the last generation. This report represents the first population-based study with a rigorous subsite analysis of OCSCC. Recently, The Cancer Genome Atlas (TCGA) released a broad molecular characterization of Head and Neck Squamous Cell Carcinoma (HNSCC) – however comparative genomics has not yet been performed on individual oral cavity subsites.

Methods: The Surveillance, Epidemiology, and End Results (SEER) database (1988–2010) was used to examine 16,298 adult cases of OCSCC. Trends in tumor subsite, staging, patient demographics, treatment characteristics, and survival over time were examined. Subsequently, data from TCGA were used to evaluate mutation, copy number, and expression profiles of clinical subgroups of interest identified by epidemiological data.

Results: The overall incidence of OCSCC decreased between 1988 and 2007, but there was a marked increase in the incidence oral tongue squamous cell carcinoma (OTSCC). There were also trends towards oral tongue (OT) cancers being diagnosed in younger individuals and at earlier stages. Five-year overall survival of OCSCC increased between 1988 and 2007 (39.9% to 50.4%, p< .01), independent of changes in patient and tumor characteristics. Much of this survival increase was specifically attributable to increases in survival of OT cancers. Multivariate analysis revealed that age, stage, and grade were important covariates with survival, but oral subsite was not. Genomic analyses aimed at characterizing OT tumors higher rates of mutation in p53 and CDKN2A, and lower rates of mutation in most other genes. CASP8 mutations were found almost exclusively in non-tongue oral subsites. OT and oral cavity (OC) cancers, even in non-smokers, did not show the characteristic molecular changes associated with Human Papillomavirus (HPV) -related cancers, but instead closely resembled traditional smoking-related tumors. Clustering analysis revealed that OT tumors possess a distinct expression signature.

Conclusions: Survival for OCSCC has improved significantly over the past 20 years. Additionally, OTSCC now has a superior 5-year survival compared to other OC subsites; this can be attributed to trends towards earlier staging and younger population. The molecular profile of OTSCC, including tumors occurring in young, non-smokers, resemble that of traditional head and neck cancers (related to environmental carcinogens) – and is very different from HPV-related oropharyngeal cancers.

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This is an Open Access Thesis.

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