Genomes and Genes
Adenocarinoma of the Lung in Women
Principal Investigator: Ann Schwartz
Abstract: DESCRIPTION: 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.
Funding Period: 2001-06-13 - 2007-05-31
more information: NIH RePORT
- Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer ConsortiumMichele L Cote
Wayne State University School of Medicine and the Karmanos Cancer Institute, Michigan, USA
Eur J Cancer 48:1957-68. 2012..Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals...
- Previous lung diseases and lung cancer risk: a pooled analysis from the International Lung Cancer ConsortiumDarren R Brenner
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
Am J Epidemiol 176:573-85. 2012..These results suggest that previous lung diseases influence lung cancer risk independently of tobacco use and that these diseases are important for assessing individual risk...
- Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO)A C Pesatori
1 EPOCA, Epidemiology Research Center, Department of Clinical Sciences and Community Health, Universita degli Studi di Milano, Via San Barnaba 8, 20122 Milan, Italy 2 Epidemiology Unit, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Via San Barnaba 8, 20122 Milan, Italy
Br J Cancer 109:1954-64. 2013..The association between oral contraceptive (OC) use, hormone replacement therapy (HRT) and lung cancer risk in women is still debated...
- Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smokingSarah H Stephens
Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States of America
Genet Epidemiol 37:846-59. 2013....
- Ordered subset analysis identifies loci influencing lung cancer risk on chromosomes 6q and 12qShenying Fang
Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
Cancer Epidemiol Biomarkers Prev 19:3157-66. 2010..Genetic susceptibility for cancer can differ substantially among families. We use trait-related covariates to identify a genetically homogeneous subset of families with the best evidence for linkage in the presence of heterogeneity...
- Survival in women with NSCLC: the role of reproductive history and hormone useHannah Katcoff
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan and Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
J Thorac Oncol 9:355-61. 2014..We evaluated the role of reproductive and hormonal factors in predicting overall survival in women with non-small-cell lung cancer (NSCLC)...
- Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25Li Shiun Chen
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA
Genet Epidemiol 36:340-51. 2012..Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments...
- Asthma and lung cancer risk: a systematic investigation by the International Lung Cancer ConsortiumAlbert Rosenberger
Department of Genetic Epidemiology, University Medical Center, Georg August University Gottingen, D 37073 Gottingen, Germany
Carcinogenesis 33:587-97. 2012....
- Genetic epidemiology of cigarette smoke-induced lung diseaseAnn G Schwartz
Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA
Proc Am Thorac Soc 9:22-6. 2012....
- The landscape of recombination in African AmericansAnjali G Hinch
Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK
Nature 476:170-5. 2011..Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution...
- Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancerMichele L Cote
Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, USA
J Thorac Oncol 6:627-30. 2011..Mutations occur more commonly in never smokers and East Asians, but there are conflicting reports on the frequency of EGFR mutations in tumors from African Americans...
- Admixture mapping of lung cancer in 1812 African-AmericansAnn G Schwartz
Karmanos Cancer Institute, Detroit, MI 48201, USA
Carcinogenesis 32:312-7. 2011..33 (P = 0.0009) at rs181696 among ever smokers with NSCLC. These results add to the findings from the GWAS in Caucasian populations and suggest novel regions of interest...
- Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African AmericansJ Matthew Reinersman
Memorial Sloan Kettering Cancer Center, New York City, New York 10065, USA
J Thorac Oncol 6:28-31. 2011..KRAS mutations confer resistance to EGFR-tyrosine kinase inhibitors. The prevalence of these mutations in African American patients has not been thoroughly investigated...
- The relationship between chronic obstructive pulmonary disease and lung cancer in African American patientsNader Mina
Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA
Clin Lung Cancer 13:149-56. 2012..Airflow obstruction and/or emphysema have been associated with lung cancer risk; however, this relationship and the joint occurrence of these conditions are not well studied in the African American population..
- Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case-control studies in the International Lung Cancer Consortium (ILCCO)Paolo Boffetta
The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA
Cancer Causes Control 22:73-9. 2011..This framework offered the opportunity to investigate the role of tobacco smoking in the development of bronchioloalveolar carcinoma (BAC), a rare form of lung cancer...
- A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokersChristopher I Amos
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA
Cancer Res 70:2359-67. 2010..These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers...
- Racial differences in the association between SNPs on 15q25.1, smoking behavior, and risk of non-small cell lung cancerAnn G Schwartz
Population Studies and Prevention Program, Karmanos Cancer Institute, Detroit, MI 48201, USA
J Thorac Oncol 4:1195-201. 2009..The goal of this study was to determine whether recently identified genetic variation in 3 SNPs (rs1051730, rs931794, rs8034191) on chromosome 15q25.1 contributes to risk of lung cancer in African Americans...
- Cytokine SNPs: Comparison of allele frequencies by race and implications for future studiesAlison L Van Dyke
Population Studies and Prevention Program, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA
Cytokine 46:236-44. 2009..Given the racial variability in allele frequencies in inflammatory gene SNPs, studies examining the association between these SNPs and disease should at least incorporate self-reported race in their analyses...
- The molecular epidemiology of lung cancerAnn G Schwartz
Population Studies and Prevention Program, Karmanos Cancer Institute, and Department of Internal Medicine, Wayne State University School of Medicine, 110 E Warren Avenue, Detroit, MI 48103, USA
Carcinogenesis 28:507-18. 2007..In the future, studies that focus on complex interactions between multiple genes and environmental exposures within pertinent pathways are needed. New technological advances in genotyping will help move the field forward...
- Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in womenAnn G Schwartz
Population Studies and Prevention Program, Karmanos Cancer Institute, 110 E Warren Ave, Detroit, MI 48201, USA
J Clin Oncol 25:5785-92. 2007..We also evaluated whether risk factors were differentially associated with cytoplasmic ER-alpha and/or nuclear ER-beta expression-defined NSCLC in postmenopausal women...
- Regular adult aspirin use decreases the risk of non-small cell lung cancer among womenAlison L Van Dyke
Cancer Biology Program, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201, USA
Cancer Epidemiol Biomarkers Prev 17:148-57. 2008..Few studies have examined the use of aspirin or other NSAIDs on risk of NSCLC in women...
- COX-2/EGFR expression and survival among women with adenocarcinoma of the lungAlison L Van Dyke
Cancer Biology Program, Karmanos Cancer Institute, WayneState University School of Medicine, Detroit, MI 48201, USA
Carcinogenesis 29:1781-7. 2008..In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung...
- Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot studyVitaly Balan
Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, USA
Cancer Res 68:10045-50. 2008..The data implicate galectin-3 H(64) in breast cancer and explain, in part, the noted racial disparity, thus providing a novel target for diagnosis and treatment...
- Development and validation of a lung cancer risk prediction model for African-AmericansCarol J Etzel
Department of Epidemiology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
Cancer Prev Res (Phila) 1:255-65. 2008..These findings highlight the importance of conducting further ethnic-specific analyses of disease risk...
- Tobacco and estrogen metabolic polymorphisms and risk of non-small cell lung cancer in womenMichele L Cote
Population Studies and Prevention Program, Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, MI 48201, USA
Carcinogenesis 30:626-35. 2009..Polymorphisms in the tobacco metabolism, estrogen metabolism and DNA repair pathways will be useful in developing more predictive models of individual risk...
- Chronic obstructive lung diseases and risk of non-small cell lung cancer in womenAnn G Schwartz
Population Studies and Prevention Program, Karmanos Cancer Institute, Detroit, MI 48201, USA
J Thorac Oncol 4:291-9. 2009..The link between lung cancer and chronic obstructive lung diseases (COPD) has not been well studied in women even though lung cancer and COPD account for significant and growing morbidity and mortality among women...
- Cytokine and cytokine receptor single-nucleotide polymorphisms predict risk for non-small cell lung cancer among womenAlison L Van Dyke
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
Cancer Epidemiol Biomarkers Prev 18:1829-40. 2009..Pathway analysis results are presented. Inflammatory pathway genotypes may serve to define a high risk group; further exploration of these genes in minority populations is warranted...
- Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sexAnn G Schwartz
Population Studies and Prevention Program, and Breast Cancer Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
Clin Cancer Res 11:7280-7. 2005..Archival lung tissue was evaluated for the presence of nuclear estrogen receptor (ER)-alpha and ER-beta and the relationship between ER status, subject characteristics, and survival...