Lung cancer continues to be the most common cancer overall and one of the leading causes of cancer death worldwide. While it is apparent that lung cancer is predominantly caused by exposure to tobacco products, only a minority of heavy smokers will develop this disease. A major source of inter-individual variability in relation to the development of cancer is likely to be DNA repair capacity. Genetic variations of DNA repair genes are thought to moderate DNA Repair Capacity (DRC), and consequently are suggested to be related to cancer risk. However, the results from epidemiological studies have been inconsistent. This is likely to be due to (i) low statistical power for detecting a moderate effect, (ii) false positive results, (iii) failure to consider effect modifiers such as environmental exposures, and (iv) publication bias. Furthermore, examining the main effects of single modest risk sequence variants is an overly simplified approach, when considering that carcinogenesis is highly complex, with numerous genes acting on multiple pathways plus their interactions with environmental factors. Moving from single marker analyses to investigation of multigenic effect and gene-environment interactions is necessary, but requires considerable sample size and statistical power. Therefore, we propose to conduct pooled analyses within the International Lung Cancer Consortium (ILCCO), a recently established international group of lung cancer researchers with the aim of sharing comparable data from ongoing lung cancer case-control and cohort studies. We will combine data from 11 studies, including 4 from US, 6 from Europe and 1 from Asia, resulting in over 10,000 cases and 12,000 controls, to evaluate the role of 19 SNPs in 11 DNA repair genes. The study hypotheses are that: (i) sequence variants in DNA repair genes confer modestly increased risks of lung cancer, (ii) a combination of multiple prior risk-genotypes confers a higher risk and (iii) genetic associations are modified by the presence of environmental exposures.
Our specific aims are 1) to investigate the independent and joint effects of 19 genetic polymorphisms in 11 DNA repair genes by pathway, 2) to assess effect modification of environmental carcinogens such as tobacco smoking, and to evaluate the contribution of SNPs, individually or in combination, to cancer risk in subgroups of particular interests, including young age of onset, rare histologies, familial cases, and never smokers, 3) to conduct relevant statistical analyses including hierarchical modeling and calculation of false positive report probabilities (FPRP), in order to address the problem of multiple comparisons, 4) to increase the efficiency of joint research by establishing a website that will publicize the resources of the consortium. We believe that our proposed analyses is a cost effective approach in generating data for a large lung cancer study, that will address the limitation of previous studies and confirm the role of these SNPs in lung carcinogenesis.
| Hung, Rayjean J; Christiani, David C; Risch, Angela et al. (2008) International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer Epidemiol Biomarkers Prev 17:3081-9 |
| Hung, Rayjean J; Baragatti, Meili; Thomas, Duncan et al. (2007) Inherited predisposition of lung cancer: a hierarchical modeling approach to DNA repair and cell cycle control pathways. Cancer Epidemiol Biomarkers Prev 16:2736-44 |
| Hung, Rayjean J; Hall, Janet; Brennan, Paul et al. (2005) Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol 162:925-42 |
