Gene-environment interaction is a seminal concept in the molecular epidemiology of human cancer. Our case-control (using hospital- and population-based controls) studies focus on lung cancer, a tobacco-related cancer. Exposure to second-hand tobacco smoke has many detrimental health effects, one of which is an increased lung cancer risk, and children may be more susceptible to the health hazards of second-hand smoke. Furthermore, alterations in the genetic background of innate immunity genes may further increase their susceptibility to lung cancer. Therefore, we hypothesized that never smokers, with specific mammose-binding lectin (MBL2) haplotypes predictive of high serum MBL levels, who are exposed to childhood second-hand smoke, may be more susceptible to developing lung cancer. We utilized the NCI-Maryland Lung Cancer Case-Control Study to investigate the association between childhood second-hand smoke and lung cancer risk. We found that the lung cancer among never smokers and among participants was associated with exposure to second-hand smoke during childhood. The MBL2 HYPA haplotype (high MBL secretor phenotype) was associated with lung cancer risk among those exposed to childhood second-hand smoke. These results were validated with an independent case-control study of never smokers from the Mayo Clinic. Lung cancer in individuals who have never smoked tobacco products is an increasing medical and public-health issue.
We aim ed to unravel the genetic basis of lung cancer in never smokers. We did a four-stage investigation. First, a genome-wide association study of single nucleotide polymorphisms (SNPs) was done with 754 never smokers (377 matched case-control pairs at Mayo Clinic, Rochester, MN, USA). Second, the top candidate SNPs from the first study were validated in two independent studies among 735 (MD Anderson Cancer Center, Houston, TX, USA) and 253 (Harvard University, Boston, MA, USA) never smokers. Third, further replication of the top SNP was done in 530 never smokers (UCLA, Los Angeles, CA, USA). Fourth, expression quantitative trait loci (eQTL) and gene-expression differences were analysed to further elucidate the causal relation between the validated SNPs and the risk of lung cancer in never smokers. 44 top candidate SNPs were identified that might alter the risk of lung cancer in never smokers. rs2352028 at chromosome 13q31.3 was subsequently replicated with an additive genetic model in the four independent studies, with a combined odds ratio of 1.46 (95% CI 1.26-1.70, p=5.94x10(-6)). A cis eQTL analysis showed there was a strong correlation between genotypes of the replicated SNPs and the transcription level of the gene GPC5 in normal lung tissues (p=1.96x10(-4)), with the high-risk allele linked with lower expression. Additionally, the transcription level of GPC5 in normal lung tissue was twice that detected in matched lung adenocarcinoma tissue (p=6.75x10(-11)). Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. Downregulation of GPC5 might contribute to the development of lung cancer in never smokers. Cell cycle checkpoints play critical roles in the maintenance of genomic integrity and inactivation of checkpoint genes, and are frequently perturbed in most cancers. In a case-control study of 299 non-small cell lung cancer cases and 550 controls in Maryland, we investigated the association between gamma-radiation-induced G2/M arrest in cultured blood lymphocytes and lung cancer risk, and examined genotype-phenotype correlations between genetic polymorphisms of 20 genes involved in DNA repair and cell cycle control and gamma-radiation-induced G2/M arrest. The study was specifically designed to examine race and gender differences in risk factors. Our data indicated that a less efficient DNA damage-induced G2/M checkpoint was associated with an increased risk of lung cancer in African American women with an adjusted odds ration (OR) of 2/63 (95% CI= 1.01 - 7.26);there were no statistically significant associations for Caucasians or African American men. When the African American women were categorized into quartiles, a significant reverse trend of decreased G2/M checkpoint function and increased lung cancer risk was present, with lowest-vs-highest quartile OR of 13.72 (95% CI = 2.30 - 81.92, P trend less than 0.01). Genotype-phenotype correlation analysis indicated the polymorphisms in ATM, CDC25C, CDKN1A, BRCA2, ERCC6, TP53, and TP53BP1 genes were significantly associated with the gamma-radiation-induced G2/M arrest phenotype. This study provides evidence that a less efficient G2/M checkpoint is significantly associated with lung cancer risk in African American women. The data also suggested that the function of the G2/M checkpoint is modulated by genetic polymorphisms in genes involved in DNA repair and cell cycle control. This is the first study to observe an association between functional polymorphisms in an innate immune system gene and lung cancer survival. Although exposure to estrogen may directly influence or modify the association between cigarette smoking and lung cancer risk, results from epidemiologic studies examining the association between reproductive and hormonal factors and risk of lung cancer among women have been inconsistent. Between 1998 and 2008, 430 women diagnosed with nonsmall cell lung cancer, 316 hospital controls and 295 population controls were recruited into the multi-center Maryland Lung Cancer Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) according to reproductive and hormonal exposures adjusting for age, smoking, passive smoking, education and household income. Results were similar for hospital and population based controls, so the control groups were combined. Reduced risks of lung cancer were observed among women with greater parity (>/=5 vs. 1-2 births: OR = 0.50, 95% CI = 0.32, 0.78, p-trend = 0.002) and later ages at last birth (>/=30 vs. <25 years old: OR = 0.68, 95% CI = 0.48, 0.98, p-trend = 0.04). After mutual adjustment parity, but not age at last birth, remained significantly inversely associated with risk (p-trend = 0.01). No associations were found for nonsmall cell lung cancer risk with age at menarche, age at first birth, menopausal status, oral contraceptive use or menopausal hormone use, including use of oral estrogens. Compatible with findings from recent epidemiologic studies, we observed a reduction in the risk of nonsmall cell lung cancer with increasing number of births. Other reproductive and hormonal exposures, including menopausal hormone therapy use, were not associated with risk.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC005480-26
Application #
8348880
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2011
Total Cost
$644,202
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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