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.
The purpose of this proposed study is to investigate the roles of genetic factors; as well as theirinteractions with tobacco and alcohol use as well as p53 mutations and HPV infections; in the etiology ofsquamous cell carcinomas of the oral cavity; pharynx; and larynx (SCCHN); expanding our findings of a novelapoptosis mechanism that has not been described before. Therefore; this study will help us understand theunderlying mechanisms of the correlation between apoptosis genotypes and phenotypes to be measured andthe roles they may play in the etiology of SCCHN. The long-term goal of this study is to identify effectivebiomarkers that can be used to identify at-risk individuals in the general population who will be targeted forprimary prevention and early detection of SCCHN.
|Guan, Xiaoxiang; Liu, Zhensheng; Wang, Luo et al. (2014) Identification of prohibitin and prohibiton as novel factors binding to the p53 induced gene 3 (PIG3) promoter (TGYCC)(15) motif. Biochem Biophys Res Commun 443:1239-44|
|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|
|Cantrell, Sarah C; Reid, Holly H; Li, Guojun et al. (2014) Influence of smoking history on imaging characteristics among patients with human papillomavirus-positive oropharyngeal cancer: a blinded matched-pair analysis. J Comput Assist Tomogr 38:667-73|
|Guo, Hongguang; Liu, Hongliang; Wei, Jianhua et al. (2014) Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck. Eur J Cancer 50:582-92|
|Xiong, Huihua; Liao, Zhongxing; Liu, Zhensheng et al. (2013) ATM polymorphisms predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys 85:1066-73|
|Wang, Li-E; Gorlova, Olga Y; Ying, Jun et al. (2013) Genome-wide association study reveals novel genetic determinants of DNA repair capacity in lung cancer. Cancer Res 73:256-64|
|Cantrell, S C; Peck, B W; Li, G et al. (2013) Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR Am J Neuroradiol 34:2005-9|
|Tucker, Susan L; Li, Minghuan; Xu, Ting et al. (2013) Incorporating single-nucleotide polymorphisms into the Lyman model to improve prediction of radiation pneumonitis. Int J Radiat Oncol Biol Phys 85:251-7|
|Guan, Xiaoxiang; Liu, Zhensheng; Liu, Hongliang et al. (2013) A functional variant at the miR-885-5p binding site of CASP3 confers risk of both index and second primary malignancies in patients with head and neck cancer. FASEB J 27:1404-12|
|Guan, Xiaoxiang; Wang, Li-E; Liu, Zhensheng et al. (2013) Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites. J Cell Mol Med 17:873-8|
Showing the most recent 10 out of 63 publications