In 1998, 80,000 women in the US were diagnosed with lung cancer and incidence rates, particularly of adenocarcinoma, continue to increase among women. Many pieces of evidence suggest that there are gender differences in susceptibility to tobacco carcinogens. Several studies have shown that DNA adducts, p53 mutations, CYP1A1 expression in the lung, and GSTM1 null genotypes are more frequent in females than in males. Reasons for differential susceptibility by gender might be explained by variations in metabolic enzyme functioning or hormonal differences. Some of the same enzymes involved in the metabolism of carcinogens in tobacco smoke are involved in the metabolism of estrogen. The goals of the proposed study are two-fold. First, we will evaluate the role of tobacco smoke and estrogens in determining risk of adenocarcinoma of the lung among women. Secondly, we will evaluate the role of estrogen receptors and c-erbB-2 in lung tumors to further understand the pathways through which estrogen may be acting in the lung.
The specific aims are: 1) To conduct a population-based case-control study of the contribution of tobacco exposure, estrogen use, and reproductive history in determining risk of adenocarcinoma of the lung in women. 716 cases will be identified through the Metropolitan Detroit Cancer Surveillance System of the Karmanos Cancer Institute (a SEER participant). An equal number of controls will be selected through random digit dialing. 2) To determine if genotype at the metabolic enzyme loci CYP1A1, CYP1B1, CYP17, CYP19, GSTM1, GSTP1, COMT, and NQO1 are associated with risk of adenocarcinoma of the lung in women. These enzymes are active in both the metabolism of tobacco smoke carcinogens and the synthesis and metabolism of estrogens. 3) To examine gene-gene and gene-environment interactions, focusing on tobacco and estrogen effects. 4) To determine estrogen receptor status (alpha and beta) and c-erbB-2 levels in the lung tumors of women with adenocarcinoma and evaluate risk associated with tobacco exposure, estrogen use, reproductive history, and genotype at metabolic enzyme loci by tumor characteristics. The proposed study represents a focused approach to defining the contribution of genes and environments in risk of adenocarcinoma of the lung in women. The interview component of the study will provide data about individually measured environmental risk factors. Genotypes have been chosen which impact on biologically effective dose of tobacco carcinogens and estrogens in the lung. The study of tumor characteristics will provide insight into mechanism of action. This large, population-based study should provide clues for important prevention and therapeutic strategies for lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087895-02
Application #
6514708
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Seminara, Daniela
Project Start
2001-06-13
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$589,718
Indirect Cost
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Jones, Carissa C; Mercaldo, Sarah Fletcher; Blume, Jeffrey D et al. (2018) Racial Disparities in Lung Cancer Survival: The Contribution of Stage, Treatment, and Ancestry. J Thorac Oncol 13:1464-1473
Jones, Carissa C; Bush, William S; Crawford, Dana C et al. (2017) Germline Genetic Variants and Lung Cancer Survival in African Americans. Cancer Epidemiol Biomarkers Prev 26:1288-1295
Ben Khedher, Soumaya; Neri, Monica; Papadopoulos, Alexandra et al. (2017) Menstrual and reproductive factors and lung cancer risk: A pooled analysis from the international lung cancer consortium. Int J Cancer 141:309-323
Fehringer, Gordon; Brenner, Darren R; Zhang, Zuo-Feng et al. (2017) Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study. Int J Cancer 140:1976-1984
Liu, Yanhong; Kheradmand, Farrah; Davis, Caleb F et al. (2016) Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer. J Thorac Oncol 11:52-61
Chen, Li-Shiun; Baker, Timothy; Hung, Rayjean J et al. (2016) Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis. EBioMedicine 11:219-226
Lusk, Christine M; Wenzlaff, Angela S; Dyson, Greg et al. (2016) Whole-exome sequencing reveals genetic variability among lung cancer cases subphenotyped for emphysema. Carcinogenesis 37:139-144
Araujo, Luiz H; Lammers, Philip E; Matthews-Smith, Velmalia et al. (2015) Somatic Mutation Spectrum of Non-Small-Cell Lung Cancer in African Americans: A Pooled Analysis. J Thorac Oncol 10:1430-6
Araujo, Luiz H; Timmers, Cynthia; Shilo, Konstantin et al. (2015) Impact of Pre-Analytical Variables on Cancer Targeted Gene Sequencing Efficiency. PLoS One 10:e0143092
Kim, Claire H; Lee, Yuan-Chin Amy; Hung, Rayjean J et al. (2015) Secondhand Tobacco Smoke Exposure and Lung Adenocarcinoma In Situ/Minimally Invasive Adenocarcinoma (AIS/MIA). Cancer Epidemiol Biomarkers Prev 24:1902-6

Showing the most recent 10 out of 44 publications