Tobacco and alcohol use and genetic susceptibility are major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Identification of susceptible individuals can effectively facilitate prevention of this disease by avoiding tobacco and alcohol use. Tobacco carcinogens cause a variety of DNA damage in the target cells, which may lead to uncontrolled cell growth, but the cells evolve to have the mechanism of programmed cell death (apoptosis), which helps eliminate cells with excessive DNA damage and thus reduce cancer risk. At least two known apoptotic pathways, the intrinsic and extrinsic, lead to cell death in response to excessive DNA damage, and there is an established flow-cytometry method to detect the apoptosis phenotype. In this new grant application, we propose to perform apoptosis phenotyping and genotyping assays in 600 newly recruited patients with SCCHN and 600 control subjects and to perform genotyping assays for an additional 1,000 SCCHN patients and 1,000 control subjects with stored DNA samples procured previously. A total of 434 common (including 88 putatively functional and 346 tagging) SNPs of 50 apoptosis-related genes have been selected and will be genotyped by using the SNPlex genotyping method for all 3,200 subjects (1,600 cases and 1,600 controls).
Our specific aims are:
AIM 1 : To determine the association between 434 common SNPs (i.e., minor allele frequency e 0.05) genotypes of 50 selected apoptosis-related genes and the risk of SCCHN. We will also detect TP53 mutations and HPV infection of a subset of 480 SCCHN patients to be prospectively recruited, aiming at identifying the most susceptible subgroups in this study population.
AIM 2 : To determine the association between the apoptotic phenotype and the risk of SCCHN.
AIM 3 : To determine the functional relevance of selected common tagging SNPs in apoptotic pathways by identifying the genotypes that predict the phenotypes. We will also explore the gene-gene and gene-environment interactions using the genotyping data from all 1,600 cases and 1,600 controls and questionnaire data that characterized the smoking history of each individual and identify the most susceptible subgroups in this study population. This proposed association study is highly hypothesis driven, expanding our preliminary data on the findings of a novel p53-PHB-PIG3 apoptosis mechanism. This study will identify genetic factors that predict the apoptotic phenotype and risk of SCCHN and thus will advance our knowledge of the etiology of SCCHN. The long-term goal of this study is to identify effective biomarkers for risk assessment and to identify at-risk individuals who can be targeted for primary prevention and early detection of SCCHN in the general population.

Public Health Relevance

The purpose of this proposed study is to investigate the roles of genetic factors, as well as their interactions with tobacco and alcohol use as well as p53 mutations and HPV infections, in the etiology of squamous cell carcinomas of the oral cavity, pharynx, and larynx (SCCHN), expanding our findings of a novel apoptosis mechanism that has not been described before. Therefore, this study will help us understand the underlying mechanisms of the correlation between apoptosis genotypes and phenotypes to be measured and the roles they may play in the etiology of SCCHN. The long-term goal of this study is to identify effective biomarkers that can be used to identify at-risk individuals in the general population who will be targeted for primary prevention and early detection of SCCHN.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131274-02
Application #
7778901
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Reid, Britt C
Project Start
2009-03-02
Project End
2014-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
2
Fiscal Year
2010
Total Cost
$634,010
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Dahlstrom, Kristina R; Anderson, Karen S; Field, Matthew S et al. (2017) Diagnostic accuracy of serum antibodies to human papillomavirus type 16 early antigens in the detection of human papillomavirus-related oropharyngeal cancer. Cancer 123:4886-4894
Zhu, Lijun; Sturgis, Erich M; Zhang, Hua et al. (2017) Genetic variants in microRNA-binding sites of DNA repair genes as predictors of recurrence in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 141:1355-1364
Lu, Zhongming; Zhang, Hua; Tao, Ye et al. (2017) MDM4 genetic variants predict HPV16-positive tumors of patients with squamous cell carcinoma of the oropharynx. Oncotarget 8:86710-86717
Liu, Hongliang; Gao, Fengqin; Dahlstrom, Kristina R et al. (2016) A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck. Tumour Biol 37:8057-66
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Wyss, Annah B; Hashibe, Mia; Lee, Yuan-Chin Amy et al. (2016) Smokeless Tobacco Use and the Risk of Head and Neck Cancer: Pooled Analysis of US Studies in the INHANCE Consortium. Am J Epidemiol :
Liu, Zhensheng; Liu, Hongliang; Gao, Fengqin et al. (2016) Reduced DNA double-strand break repair capacity and risk of squamous cell carcinoma of the head and neck--A case-control study. DNA Repair (Amst) 40:18-26
Guan, Xiaoxiang; Liu, Hongliang; Ju, Jingfang et al. (2015) Genetic variant rs16430 6bp > 0bp at the microRNA-binding site in TYMS and risk of sporadic breast cancer risk in non-Hispanic white women aged ? 55 years. Mol Carcinog 54:281-90
Wen, Juyi; Liu, Hongliang; Wang, Qiming et al. (2014) Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. Eur J Cancer 50:1706-16

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