Lung Cancer Research
Distribution and Determinants of Lung Cancer Risk, Survivorship and Outcomes
COPD & Lung Cancer
Inflammation is likely to play a role in lung cancer development given the chronic exposure to tobacco smoke. Program members have shown that a history of COPD is associated with increased risk of lung cancer. Their work also suggested racial differences in this association, with African Americans less likely to report a COPD diagnosis and lower lung cancer risk than whites. Further examination of medical records for African Americans showed significant under-reporting or under-diagnosis of COPD. Comparing medical records to self-report, 78% of the lung cancer cases not reporting COPD during an interview had spirometry or CT evidence of COPD. When both spirometry and CT data were available, 29% of the cases have CT evidence of emphysema but normal spirometry. Program members are leading a study to further evaluate the relationship between lung cancer risk and COPD by race and the mechanisms underlying this increased risk. This study includes spirometry and CT measures of the COPD phenotype, is evaluating quantitative imaging methods as measures of COPD, genotyping inflammatory pathway genes and evaluating gene expression in normal and tumor tissue.
- Lead Researchers: Drs. Schwartz, Cote and Gadgeel
- Collaborative Researchers: Dr. Spitz, Baylor Univeristy
- Grant: R01 CA141769
Genetic Links to Lung Cancer
Family risk of lung cancer and inherited susceptibility continue to be a focus of our research. Leading an International Lung Cancer Consortium pooled analysis of 24,380 lung cancer cases and 23,305 controls, program members reported an approximately 1.5-fold increased risk of lung cancer in individuals with a first degree family history of the disease. Risk did not vary with histologic type. Risk was not quite as high in never smokers (OR=1.25), but remained statistically significant. While the underlying genetic cause of inherited risk is not yet defined, family history assessment is immediately available as a tool to better define a high risk group. Using the family as a point of entrée for behavior change, program members are investigating family dynamics surrounding smoking behaviors and lung cancer risk. The Genetic Epidemiology of Lung Cancer Consortium (GELCC) has demonstrated linkage on chromosome 6q, with smoking associated risk varying by risk haplotype. Smoking associated risk demonstrated the expected dose-response relationship in individuals in families without the risk haplotype, while for individuals in families with the risk haplotype, risks were more uniform across smoking strata, with particularly higher risks of never and light smokers.
- Lead Researchers: Drs. Cote and Schwartz
- Collaborative Researchers: Drs. Harper and Manning
- Grant: U19 CA148127
Metropolitan Detroit is home to some of the highest lung cancer rates in the country, especially among African Americans. In the search for susceptibility genes for lung cancer, program members have used admixture mapping in African Americans, taking advantage of the genetic architecture in admixed populations. Multiple regions were identified that differentially associated with founding population. These regions were included in a replication study that included African American cases and controls from Wayne State University/Karmanos Cancer Institute, MD Anderson Cancer Center and University of San Francisco. While none of the admixture regions were replicated, members did fine map several regions previously identified in GWAS in whites in our large African American population and identified a novel CHRNA1 susceptibility locus.
The large number of lung cancer studies and focus on minority accrual has allowed program members to contribute to a number of collaborative studies linking smoking onset and heavy smoking to chromosome 15q25. In addition, the data and biospecimens collected in African Americans are being used in a lung cancer GWAS lead by Dr. Chanock at the National CI, with findings reported for non-cancer outcomes such as genetic recombination in African Americans, clonal mosaicism and aging and BMI.
- Lead Researcher: Dr. Schwartz
- Grant: R01 CA60691
The identification of driver mutations and genetic alterations in EGFR and ALK has led to successes in lung cancer outcomes using targeted treatment. While The Cancer Genome Atlas (TCGA) has done a remarkable job profiling mutations in lung tumors and continues to provide an avenue for the identification of driver mutations, only 27 adenocarcinomas and 17 squamous cell carcinomas from African Americans. African Americans have lower pack-years of smoking exposure but higher incidence of lung cancer and poorer outcomes than whites. Program members have examined somatic mutations in lung tumors from diverse populations Among African Americans with non-small cell lung cancer (NSCLC). Program member reported the frequency of EGFR mutations was similar to that among whites, however all mutations in African American patients were deletions in exon 19. This inter-programmatic collaboration also demonstrated a 3.5-fold amplification of FGFR1 in NSCLC is associated with patient survival. In an expanded case series of African Americans with NSCLC, 214 somatic mutations in 26 genes, including EGFR, KRAS, BRAF, MAP2K1, EPHA3, NTRKs, STK11 and DDR2, were evaluated. Mutations were identified in 41% of white patients and only 32% of African American patients. Tumors from African American patients were less likely to be KRAS mutated and, among women, EGFR mutations were 3.9-fold higher in African Americans than whites. Four percent of African Americans and 7% of whites had tumors with two known mutations.
Estrogen & Lung Cancer
Male-female differences in lung cancer risk, tumor characteristics and outcome have fueled investigations into the role of estrogens in lung cancer risk and prognosis. Program members have participated in the evaluation of the role of hormone therapy in lung cancer development and survival in Women’s Health Initiative (WHI) clinical trials. Estrogen alone was not found to increase lung cancer risk or death from lung cancer based on Women’s Health Initiative data. A joint analysis of the WHI observational data plus clinical trial data, is underway to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk. The International Lung Cancer Consortium reported that both oral contraceptive users and hormone replacement users (both estrogen alone and estrogen plus progesterone) had a reduced risk of lung cancer. Program members reported recently that use of hormone replacement was associated with improved survival after a lung cancer diagnosis.
- Lead Researcher: Dr. Schwartz
Intervention Research with the Middle Eastern/Arab Americans to Reduce and Eliminate Disparities
Middle Eastern Americans Smoking and Lung Cancer
Metropolitan Detroit has the largest population of Middle Eastern/Arab Americans numbering more than 400,000 residents. Given the growing practice of water pipe (WP) smoking, especially among Arab American adolescents, Dr. Rice and colleagues are studying the little known effects of such risk behavior. Compared to cigarette smokers, they expect that WP smoking significantly diminishes lung function and increases health problems among youth. They also expect to see differing patterns, frequency, and intensity of WP use, yet similar or worse health problems as outcomes. The study sites include three public high schools in the Karmanos' catchment area. A detailed water pipe and cigarette smoking "life time" history of tobacco use has been obtained from nearly 3000 high school seniors. The 300 students with the longest and most severe water pipe and/or cigarette smoking histories have been asked to participate in saliva cotinine testing (to verify their smoking status) and pulmonary function testing. These students will be compared with nonsmokers matched on key pulmonary function variables (age, gender, height, and ethnicity). The analyses will estimate the effects of smoking status on spirometry outcomes.
- Lead Researcher: Dr. Rice
- Grant: R15 DA032822