Anil Chaturvedi

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NCI, DCEG, IIB

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PLCO (Learn more about this study)

2009-0516

Jun 10, 2009

Chronic Inflammation and Risk of Lung Cancer

Lung cancer is the most common cancer worldwide. While smoking is the dominant risk factor, other co-factors could contribute to lung carcinogenesis. Chronic pulmonary inflammation could act as a co-factor to tobacco carcinogens in increasing lung cancer risk. Previous studies investigating the role of chronic inflammation have focused on a narrow range of systemic inflammatory markers. Therefore, the precise inflammatory pathways or biomarkers involved in lung carcinogenesis are as yet unknown. Additionally, it is unclear whether elevated systemic inflammatory markers reflect local pulmonary inflammation. No study to date has assessed systemic as well as local markers of pulmonary inflammation/ fibrosis in conjunction. Our recent studies within the screening arm of the PLCO trial support an etiologic role for chronic inflammation in lung cancer. In these studies, we observed that elevated systemic C-reactive protein (CRP) levels, evidence of chronic Chlamydia pneumoniae infection, and pulmonary scarring/fibrosis on T0 chest radiographs were associated with significantly increased lung cancer risk. In the current application, we propose to comprehensively evaluate the role of chronic inflammation in lung cancer by measuring a wide range of systemic inflammatory markers and characterizing inflammation in lung cancer and surrounding normal tissues. Among 592 cases and 670 controls who participated in the PLCO trial's screening arm, we will measure circulating levels of 42 markers, including pro-inflammatory cytokines, anti-inflammatory cytokines, chemokines, growth factors, and angiogenesis factors. We will characterize the presence of inflammation in lung cancer tumors and surrounding normal tissues by assessing the cellular milieu and measuring expression of CRP and cycloxygenase-2. We will also extend our previous observation of a serologic association of C. pneumoniae with lung cancer by assessing the presence of C. pneumoniae organisms in lung cancer tumors. Finally, in a larger sample enriched with additional 150 controls with radiographic findings suggestive of pulmonary fibrosis/scarring, we will examine serum markers of interstitial lung disease and pulmonary fibrosis in relation to chest radiographic findings and lung cancer risk. Non-Hodgkin lymphoma (NHL) is the 6th most common cancer in U.S. men and women. Known risk factors including severe immunosuppression do not account for the majority of cases. Chronic immune stimulation by infectious agents such as hepatitis C virus (HCV) is thought to play a role in the development of lymphoma. There is a growing interest in the association between GB virus type C (GBV-C) and NHL due to its similarities to HCV and its ability to replicate in B-cells. GBV-C is transmitted through blood, including transfusions and sexually, and is detected in 1-2% of healthy blood donors. A recent population-based case-control study reported a positive association (OR=2.7, 95% CI 2.1-13.7) between GBV-C RNA in serum/plasma and NHL. The next step is to confirm this association in a prospective design in order to minimize selection bias in controls, mitigate disease and treatment effects on GBV-C status, as well as to evaluate, through the use of serial samples, whether persistence of the virus leads to increased risk of NHL. If the association between GBV-C and NHL is confirmed, there may be important implications for screening blood donors.We propose to test for active and past infection with GBV-C in follow-up serum samples (proximal to disease diagnosis/control selection) from 536 NHL cases and 1,072 controls (frequency-matched by age, sex, ethnicity, and time from baseline to diagnosis/selection) enrolled in the screening arm of PLCO in order to evaluate whether active or past infection with GBV-C is associated with subsequent NHL risk. If we find an association between GBV-C RNA positivity and NHL, we propose to test baseline serum in individuals who tested positive for GBV-C RNA to evaluate whether persistent infection may explain the association. Examining the association between GBV-C and NHL in a large, prospective cohort is timely, may have important public health implications, and may help further elucidate the etiology of NHL.