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Immunity, Inflammation, and DNA repair in Lung Cancer

Principal Investigator
Name
Sharon Pine
Degrees
-
Institution
UMDNJ/ Cancer Institute of New Jersey
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2006-0297
Initial CDAS Request Approval
Dec 29, 2006
Title
Immunity, Inflammation, and DNA repair in Lung Cancer
Summary
There is emerging evidence that chronic inflammation in the lung is causally related to lung cancer risk. Genetic variants which influence the activity or expression of inflammatory mediators may be related to lung cancer susceptibility. We propose a nested case-control study within the screening arm of the prospective PLCO cohort to investigate the hypothesis that inflammation and innate immunity pathways modulate lung cancer risk and prognosis, and effects of these pathways are amplified in conjunction with reduced DNA repair capacity. To examine the role of inflammation and innate immunity on lung cancer, we will study the association of cytokine levels, innate immunity proteins in serum and genetic polymorphisms in these pathways with lung cancer and survival. Given that obesity is associated with chronic inflammation, the association of obesity with lung cancer will be studied within the inflammation context. Chronic inflammation results in excessive oxygen and nitrogen free radicals that are known to induce DNA damage. Therefore, we will investigate whether reduced DNA repair capacity, measured by polymorphisms in DNA repair genes, is associated with lung cancer in study participants with high levels of pro-inflammatory cytokines or those with genetic variants in inflammation or immunity pathways. The selection of inflammatory and immunity markers, and polymorphisms in DNA repair genes is based on results from preliminary studies. The results of our proposed study will potentially identify biological markers of lung cancer susceptibility and may aid in the identification of populations at greater risk for lung cancer in order to more efficiently target lung cancer prevention and screening programs. Our results may also identify lung cancer patients with a poorer outcome who could be targeted for novel aggressive therapeutic trials.
Aims

We hypothesize that inflammation and innate immunity pathways are involved in lung cancer risk and survival, and the effects are modulated by defects in DNA repair pathways. The specific aims designed to test the central hypothesis are: E.2.1 To examine polymorphisms in genes involved in innate immunity and inflammation. This will be achieved by genotyping key polymorphisms in MBL, and CRP, and the cytokine genes IL-1b, IL-4, IL-6, IL-8, TNFa and TGFb1. Polymorphisms (individual and combinations) will be assessed for their association with lung cancer risk and survival. E.2.2 To measure inflammatory markers in serum. This will be accomplished by ELISA analysis of MBL, CRP, IL-1b, IL-6, and IL-8 proteins. Cytokine levels will be compared to genotypic data of the corresponding gene, and will be assessed for their association with lung cancer risk and survival. E.2.3 To examine polymorphisms in genes in the DNA repair pathways. This will be performed by genotyping polymorphisms in the ATM, XPD, and WRN genes. The association of key single nucleotide polymorphisms (SNPs) within these genes with lung cancer risk and survival will be examined, as well as their interaction with the immunity and inflammation-related SNPs and serum cytokine levels. E.2.4 To study the effect of body-mass-index (BMI) on lung cancer risk and survival and its relationship to inflammation pathways. The PLCO basic questionnaire allows us to correlate participant BMI at the start of the prospective study, and at the age of 20. BMI will be correlated to the immunity-related SNPs and cytokine levels and it will be assessed for its association with lung cancer risk and survival

Collaborators

Stephen Chanock (CGF, NCI)
Curtis Harris (LHC, CCR, NCI)
Lindsay Enewold (Georgetown University)
Leah Mechanic (LHC, CCR, NCI)
Susan Olivo-Marston (LHC, CCR, NCI)
Sharon Pine (NCI)

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