The Role of Chronic Inflammation in the Development of Lung Cancer

• Main Author: Brenner, Darren
• Other Authors: Hung, Rayjean
• Language: en_ca
• Published: 2012
• Subjects: Epidemiology; Lung Cancer; 0766
• Online Access: http://hdl.handle.net/1807/33939

Inflammation is believed to play a pivotal role in the development of cancer and in particular lung cancer through both intrinsic and extrinsic pathways. This thesis aimed through 4 manuscripts to determine the role of lung-specific inflammation-related exposures as well as genetic variants (Single Nucleotide Polymorphism (SNPs)) in genes related to inflammation pathways in lung cancer risk. Risk factors of particular interest were lung diseases including emphysema, chronic bronchitis, pneumonia and tuberculosis. Data were collected from a Toronto-based case-control study and combined with data from the International Lung Cancer Consortium (17 studies for the non-genetic analyses and 6 studies for the genetic analyses). For non-genetic data, methods included, but were not limited to, unconditional logistic regression within single studies, Cox proportional hazards regression, meta-analytic techniques and pooled analyses techniques. For genetic data, additive models of association across 7,650 SNPs (selected based on role in inflammation) were pooled across studies and hierarchical modeling iv (HM) was used to incorporate prior functional information from various sources concerning the SNPs of interest. Within the Toronto study (manuscript 1) associations with increased lung cancer risk were observed for occupational exposures, previous lung diseases and a family history of cancer. The meta-analysis (manuscript 2) and pooled analysis (manuscript 3) showed relatively consistent associations between previous lung diseases and lung cancer risk across histology, gender and smoking categories. Results persisted when examining lung disease diagnoses made >10 or >20 years before cancer diagnosis. Our pathway-based analysis of inflammation-related variants and lung cancer risk using HM (manuscript 4) showed that HM is applicable to SNP analysis using pooled designs where heterogeneity can be incorporated into SNP priors. After HM a previously observed variant (rs2736100) and novel variant (rs2741354) were observed to be associated with lung cancer risk at corrected levels and replicated in an independent population. Taken together these results provide further evidence of both intrinsic and extrinsic factors affecting risk of lung cancer through inflammation.