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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100679-09
Application #
8213633
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Reid, Britt C
Project Start
2003-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$314,607
Indirect Cost
$120,405
Name
Brown University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Galeone, Carlotta; Edefonti, Valeria; Parpinel, Maria et al. (2015) Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer 136:904-14
Kelsey, Karl T; Nelson, Heather H; Kim, Stephanie et al. (2015) Human papillomavirus serology and tobacco smoking in a community control group. BMC Infect Dis 15:8
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Edefonti, Valeria; Hashibe, Mia; Parpinel, Maria et al. (2015) Natural vitamin C intake and the risk of head and neck cancer: A pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer 137:448-62
Galeone, Carlotta; Turati, Federica; Zhang, Zuo-Feng et al. (2015) Relation of allium vegetables intake with head and neck cancers: evidence from the INHANCE consortium. Mol Nutr Food Res 59:1641-50
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Langevin, Scott M; Kratzke, Robert A; Kelsey, Karl T (2015) Epigenetics of lung cancer. Transl Res 165:74-90
Fogleman, E V; Eliot, M; Michaud, D S et al. (2015) Occupational asphalt is not associated with head and neck cancer. Occup Med (Lond) 65:570-3

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