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Grant Details

Grant Number: 5R01CA131274-04 Interpret this number
Primary Investigator: Wei, Qingyi
Organization: University Of Tx Md Anderson Can Ctr
Project Title: Genotypes and Phenotypes of Apoptosis and Risk of Head and Neck Cancer
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): 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.

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Publications

Influence of smoking history on imaging characteristics among patients with human papillomavirus-positive oropharyngeal cancer: a blinded matched-pair analysis.
Authors: Cantrell SC, Reid HH, Li G, Wei Q, Sturgis EM, Ginsberg LE
Source: J Comput Assist Tomogr, 2014 Sep-Oct;38(5), p. 667-73.
PMID: 24943254
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Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy.
Authors: Wen J, Liu H, Wang Q, Liu Z, Li Y, Xiong H, Xu T, Li P, Wang LE, Gomez DR, Mohan R, Komaki R, Liao Z, Wei Q
Source: Eur J Cancer, 2014 Jul;50(10), p. 1706-16.
EPub date: 2014 Apr 26.
PMID: 24780874
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Identification of prohibitin and prohibiton as novel factors binding to the p53 induced gene 3 (PIG3) promoter (TGYCC)(15) motif.
Authors: Guan X, Liu Z, Wang L, Johnson DG, Wei Q
Source: Biochem Biophys Res Commun, 2014 Jan 24;443(4), p. 1239-44.
EPub date: 2014 Jan 3.
PMID: 24388982
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Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck.
Authors: Guo H, Liu H, Wei J, Li Y, Yu H, Guan X, Li-E W, Li G, Sturgis EM, Wei Q, Liu Z
Source: Eur J Cancer, 2014 Feb;50(3), p. 582-92.
EPub date: 2013 Nov 29.
PMID: 24295637
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Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma.
Authors: Zhang Y, Sturgis EM, Dahlstrom KR, Wen J, Liu H, Wei Q, Li G, Liu Z
Source: Cancer Res, 2013 Oct 1;73(19), p. 5996-6003.
EPub date: 2013 Aug 8.
PMID: 23928994
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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.
Authors: Guan X, Wang LE, Liu Z, Sturgis EM, Wei Q
Source: J Cell Mol Med, 2013 Jul;17(7), p. 873-8.
EPub date: 2013 Jun 7.
PMID: 23742673
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The miR-184 binding-site rs8126 T>C polymorphism in TNFAIP2 is associated with risk of gastric cancer.
Authors: Xu Y, Ma H, Yu H, Liu Z, Wang LE, Tan D, Muddasani R, Lu V, Ajani JA, Wang Y, Wei Q
Source: PLoS One, 2013;8(5), p. e64973.
EPub date: 2013 May 28.
PMID: 23724109
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Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis.
Authors: Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM, Ginsberg LE
Source: AJNR Am J Neuroradiol, 2013 Oct;34(10), p. 2005-9.
EPub date: 2013 May 9.
PMID: 23660291
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Incidence and pattern of second primary malignancies in patients with index oropharyngeal cancers versus index nonoropharyngeal head and neck cancers.
Authors: Gan SJ, Dahlstrom KR, Peck BW, Caywood W, Li G, Wei Q, Zafereo ME, Sturgis EM
Source: Cancer, 2013 Jul 15;119(14), p. 2593-601.
EPub date: 2013 Apr 19.
PMID: 23605777
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Polymorphisms of nucleotide excision repair genes predict melanoma survival.
Authors: Li C, Yin M, Wang LE, Amos CI, Zhu D, Lee JE, Gershenwald JE, Grimm EA, Wei Q
Source: J Invest Dermatol, 2013 Jul;133(7), p. 1813-21.
EPub date: 2013 Feb 14.
PMID: 23407396
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Association between putative functional variants in the PSMB9 gene and risk of melanoma--re-analysis of published melanoma genome-wide association studies.
Authors: Qian J, Liu H, Wei S, Liu Z, Li Y, Wang LE, Chen WV, Amos CI, Lee JE, GenoMEL investigators, Iles MM, Law MH, Q-MEGA AMFS investigators, Cust AE, Barrett JH, Montgomery GW, Taylor J, Bishop JA, Macgregor S, Bishop DT, Mann GJ, Hayward NK, Wei Q
Source: Pigment Cell Melanoma Res, 2013 May;26(3), p. 392-401.
EPub date: 2013 Mar 27.
PMID: 23360169
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Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk.
Authors: Liu H, Wang LE, Liu Z, Chen WV, Amos CI, Lee JE, Q-MEGA and AMFS Investigators, GenoMEL Investigators, Iles MM, Law MH, Barrett JH, Montgomery GW, Taylor JC, MacGregor S, Cust AE, Newton Bishop JA, Hayward NK, Bishop DT, Mann GJ, Affleck P, Wei Q
Source: Carcinogenesis, 2013 Apr;34(4), p. 885-92.
EPub date: 2013 Jan 4.
PMID: 23291271
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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.
Authors: Guan X, Liu Z, Liu H, Yu H, Wang LE, Sturgis EM, Li G, Wei Q
Source: FASEB J, 2013 Apr;27(4), p. 1404-12.
EPub date: 2012 Dec 27.
PMID: 23271051
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