In the United States this year, almost 40,000 new cases of head and neck squamous cell carcinoma (HNSCC) will be diagnosed, and approximately 11,000 deaths will result from this disease. Alcohol use and tobacco smoking act synergistically in causing this disease, although exposure to the human papilloma virus (HPV) is now also linked to HNSCC risk. In addition to risks related to exposures and lifestyle factors, susceptibility for HNSCC has been linked to polymorphic variation in key genes important to a number of cellular processes related to carcinogenesis. However, overall, the mechanism responsible for induction of the cellular changes that give rise to HNSCC remains incompletely understood and novel approaches are needed to further advance our knowledge. In the post-genomic era, epigenetic regulation has emerged as critical mode by which the expression of genes can be controlled. DNA CpG island methylation, a specific and well studied epigenetic mark, can lead to inactivation of a gene in a heritable and stable fashion. Recent work has suggested that there are systematic differences in the carcinogenic exposures that induce distinct classes of alterations in cancer cells. The current proposal is based upon a new paradigm stating that variation in exposure is associated with predictable differences in somatic alteration to the cancer cell epigenome. We believe that investigating this paradigm may yield powerful markers of susceptibility for human cancer. Specifically, we hypothesize that there are distinct subgroups of HNSCCs characterized by a predominant phenotype that can be broadly grouped as displaying genetic alterations or epigenetic alterations. Further, our data suggest that environmental, lifestyle and viral (HPV) factors significantly drive these phenotypes. We will apply molecular epidemiologic methods to examine this hypothesis, utilizing the resources of an existing, population-based case control study of HNSCC.
The aims of this project are to study all of the cancers collected from volunteers in the parent study and to identify subgroups of tumors where (1) somatic genetic deletion events predominate or (2) somatic DNA methylation silencing (epigenetic events) predominates. We will examine how differences in methylation and deletion of critical DNA regions associate with smoking exposure, alcohol use and dietary deficiencies in driving oral carcinogenesis. We will further use a pathway approach to ask if there are normal genetic polymorphisms that interact with these somatic events, predisposing individuals to susceptibility to either particular type of cancer associated somatic change. All of this will be completed using validated, high- throughput methodologies. Using this novel approach, this data will aid in identifying the carcinogenic mechanisms associated with susceptibility to the carcinogenic activities of alcohol, smoking, and dietary deficiencies.

Public Health Relevance

This project "Patterns of Somatic Gene Alterations in Oral Cancer" will investigate the relationship of the major risk factors for Head and Neck cancers with the pattern of inactivation of the major genes responsible for causing these tumors. We believe that the underlying patterns of gene changes may predict disease outcome and lead to new understanding of this cancer, enhancing our ability to both prevent and treat the disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Epidemiology of Cancer Study Section (EPIC)
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Reid, Britt C
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Brown University
Public Health & Prev Medicine
Schools of Public Health
United States
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Tan, Xinmiao; Nelson, Heather H; Langevin, Scott M et al. (2015) Obesity and head and neck cancer risk and survival by human papillomavirus serology. Cancer Causes Control 26:111-9
Langevin, Scott M; Kratzke, Robert A; Kelsey, Karl T (2015) Epigenetics of lung cancer. Transl Res 165:74-90
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Accomando, William P; Wiencke, John K; Houseman, E Andres et al. (2014) Quantitative reconstruction of leukocyte subsets using DNA methylation. Genome Biol 15:R50
Michaud, Dominique S; Langevin, Scott M; Eliot, Melissa et al. (2014) High-risk HPV types and head and neck cancer. Int J Cancer 135:1653-61
Leoncini, Emanuele; Ricciardi, Walter; Cadoni, Gabriella et al. (2014) Adult height and head and neck cancer: a pooled analysis within the INHANCE Consortium. Eur J Epidemiol 29:35-48
Marks, Morgan A; Chaturvedi, Anil K; Kelsey, Karl et al. (2014) Association of marijuana smoking with oropharyngeal and oral tongue cancers: pooled analysis from the INHANCE consortium. Cancer Epidemiol Biomarkers Prev 23:160-71
Koestler, Devin C; Christensen, Brock C; Marsit, Carmen J et al. (2013) Recursively partitioned mixture model clustering of DNA methylation data using biologically informed correlation structures. Stat Appl Genet Mol Biol 12:225-40
Eliot, Melissa N; Michaud, Dominique S; Langevin, Scott M et al. (2013) Periodontal disease and mouthwash use are risk factors for head and neck squamous cell carcinoma. Cancer Causes Control 24:1315-22
Langevin, Scott M; Michaud, Dominique S; Marsit, Carmen J et al. (2013) Gastric reflux is an independent risk factor for laryngopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 22:1061-8

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