Lung cancer is the leading cause of cancer-related mortality in the U.S. and the world. The genetic factors that commonly influence lung cancer susceptibility have not yet been investigated thoroughly, but eight genome-wide association studies have been performed. In area 1 of our response, we propose to integrate data from these eight studies that comprise over 13,000 lung cancer cases and 25,000 controls to increase power to detect genetic factors influencing all types of lung cancer and to allow us to analyze specific subsets, such as cases with early onset, specific histological sets, gender-defined groups and never smokers and the extended sample size will allow us to study gene-environment interactions. Existing genome wide association studies have not analyzed data from non-Caucasian ethnic backgrounds and we therefore propose characterizing and fine mapping genetic factoid In 1500 African-American and 1500 Asian case-control pairs along with an additional 3000 Caucasian case-control pairs. We will then replicate our findings in a broader collection of an additional 12,000 case-control pairs. In area 2, we will evaluate genes in specific loci including nicotinic acetycholine receptor subunits CHRNA5 and CHRNA3 for the effects that identified SNPs from area 1 have upon these genes functions. We will also study several other loci that have been identified through existing GWAS as strongly associated with lung cancer risk, including PSMA4, hTERT, CLPT1 ML, BAT3, and hMSHS. For each of these genes, we will study modulation of these genes using cellular models relevant to their known functions. In area 3, we propose epidemiological characterization of genetic and environmental risk factors for lung cancer. We will characterize mechanisms by which variation in the loci identified in area 1 influence risk, in conjunction with smoking and other exposures. We will also evaluate the calibration of existing risk prediction models for lung cancer and then develop new models based upon genetic and environmental data from this initiative. The overarching goal of our proposal is the identification of individuals at high risk for lung cancer development for whom screening and early detection would be most beneficial in reducing the burden of lung cancer.

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Our proposal will combine existing genome-wide association data from over 13,000 lung cancer cases and 25,000 controls. We will analyze these data jointly to identify novel genetic factors and gene-environment interactions that influence risk for lung cancer and evaluate biological mechanisms by which they cause lung cancer We will evaluate joint effects of smoking and genetic factors in diverse populations.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZCA1-SRLB-4 (J1))
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Gillanders, Elizabeth
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University of Texas MD Anderson Cancer Center
Schools of Medicine
United States
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Allen, Julie K; Armaiz-Pena, Guillermo N; Nagaraja, Archana S et al. (2018) Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res 78:3233-3242
Sandanger, Torkjel Manning; Nøst, Therese Haugdahl; Guida, Florence et al. (2018) DNA methylation and associated gene expression in blood prior to lung cancer diagnosis in the Norwegian Women and Cancer cohort. Sci Rep 8:16714
Ji, Xuemei; Bossé, Yohan; Landi, Maria Teresa et al. (2018) Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat Commun 9:3221
Gorlov, Ivan P; Pikielny, Claudio W; Frost, Hildreth R et al. (2018) Gene characteristics predicting missense, nonsense and frameshift mutations in tumor samples. BMC Bioinformatics 19:430
Wang, Zhaoxi; Wei, Yongyue; Zhang, Ruyang et al. (2018) Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma. EBioMedicine 32:93-101
Ferreiro-Iglesias, Aida; Lesseur, Corina; McKay, James et al. (2018) Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity. Nat Commun 9:3927
Hancock, D B; Guo, Y; Reginsson, G W et al. (2018) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry 23:1-9
Feng, Yun; Wang, Yanru; Liu, Hongliang et al. (2018) Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer. Mol Carcinog 57:216-224
Li, Yafang; Xiao, Xiangjun; Han, Younghun et al. (2018) Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population. Carcinogenesis 39:336-346
Seow, Wei Jie; Matsuo, Keitaro; Hsiung, Chao Agnes et al. (2017) Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations. Hum Mol Genet 26:454-465

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