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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

DNA methylation patterns and lung cancer risk prediction

Awarded: NOK 4.0 mill.

1. Biomarkers and Lung Cancer Risk Reduction Lung cancer is the leading cause of cancer death world-wide. More than 1.6 million people die from lung cancer every year. The strongest risk factor for lung cancer is tobacco smoke exposure. The best way to prevent lung cancer is to reduce tobacco smoking. However, many people who no longer smoke, or never smoked at all, are now being diagnosed with lung cancer. The first part of this project assessed if nutritional biomarkers, including Vitamin B12 and Vitamin D, could inform safe and cost-effective interventions to reduce lung cancer risk. Other biomarkers studied in this project included cotinine, high-sensitivity C-reactive protein (hs-CRP), and circulating markers of cellular immune activation including tryptophan, kynurenine, quinolinic acid, and neopterin. Our findings support the hypothesis that high Vitamin B12 status increases the risk of lung cancer, whilst low Vitamin D status had no association with lung cancer risk. As expected, higher serum cotinine concentrations were well correlated with lung cancer risk as were higher circulating hs-CRP concentrations. Finally, the highest quintile s of kynurenine, kynurenine:tryptophan ratio, quinolinic acid and neopterin were associated with a 20% - 30% increased risk of lung cancer. However, tryptophan was associated with a 15% lower risk of lung cancer. 2. Cost-effectiveness of biomarker based CT-screening for lung cancer There are four stages to lung cancer, early stage disease (stage I and II), and late stage disease (stage III and IV). Many people are diagnosed with lung cancer at the later stages when mortality from lung cancer is very high. We can have a major impact on lung cancer mortality if more lung cancer patients can be diagnosed at earlier stages of disease. One way to catch the disease earlier is to find biomarkers that can predict a person's risk of lung cancer. The second part of this project assessed whether biomarker-based lung cancer screening could help refine CT-screening eligibility by predicting lung cancer risk in a cost-effective manner. Our results suggest that using biomarkers to optimise selection of ever smokers into lung cancer screening can be cost-effective under some scenarios. However, this exploratory analysis cannot provide sufficient evidence for price setting or decision-making, but this work does support the pursuit of additional research on biomarker informed eligibility for lung cancer screening. 3. Epidemiology and risk factors for kidney cancer The cause of kidney cancer is largely unknown and only a few risk factors for kidney cancer have been confirmed. We report on established risk factors for kidney cancer including tobacco smoking, body size , and history of hypertension and chronic kidney disease. We stress the importance of new methods within the field of molecular epidemiology - including metabolomics and tumor genomics - in identifying some of the underlying causes of kidney cancer. 4. Metabolomics of kidney cancer Metabolomics studies the concentration of small molecules in the human body, for example, sugars, lipids, and amino acids. The metabolome is the complete set of metabolites within a cell, or tissue at any specific time point. Metabolomics can also be used to identify biomarkers for disease state, including kidney cancer. Using data from 5 independent European cohorts, we identified 25 metabolites strongly associated with risk of kidney cancer. The risk profile of some - but not all - of these metabolites were related to body mass index.

Lung cancer is the leading cause of cancer death world-wide, and is responsible for 1.4 million deaths annually. In 2008, there were over 1.6 million new cases of lung cancer. The main determinant of lung cancer is tobacco exposure and the primary and most important means for lung cancer control is through reducing tobacco smoking. Still, the lifetime risk of lung cancer among former smokers remains high. Close to 50% of lung cancer cases now occur among former and never smokers. Lung cancer survival rate is poor, with a 5-year mortality rate of approximately 85%. Given the overall poor survival rates among diagnosed lung cancer cases, and the notable risk experienced by current, former and never smokers, identifying additional factors that may help to reduce the risk of lung cancer should be given a high priority. This may be particularly relevant for former smokers who seek additional means to further reduce their lung cancer risk. Furthermore, increasing the proportion of cases diagnosed with early stage disease (stage I and II) could have a major impact on overall lung cancer mortality. The overarching objective of this post-doctoral project is to conduct cancer research for cancer prevention by evaluating if the one-carbon metabolism (OCM) pathway affects lung cancer risk through epigenetic alterations. This project is designed with a strong emphasis on biostatistics, bioinformatics and epidemiology and will benefit from a large sample size, which will enable the evaluation of important sub-groups, including former and never smokers. If B-vitamins in the OCM pathway are proven to be important in lung cancer aetiology, our results may inform a safe and cost-effective nutritional intervention to reduce lung cancer risk, over and above quitting smoking. If methylation signatures improve risk prediction models for lung cancer, our results may refine CT-screening eligibility criteria, improve screening efficacy, and help to further reduce lung cancer mortality.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering