Large international study identifies genetic predisposition to lung cancer
In a paper published in the April 3 edition of Nature*, a worldwide consortium of investigators present a major breakthrough for understanding the genetic basis of lung cancer. The international team of investigators have uncovered for the first time an important genetic region that is associated with lung cancer risk and helps to understand the process by which tobacco smoking can cause this cancer. The findings are based on the l argest genetic study of lung cancer ever conducted, involving over 10000 people, about half of whom had lung cancer, and was led by the International Agency for Rese arch on Cancer based in Lyon, France, and two leading French institutes : the Centre National de Génotypage (CEA) based in Evry, and the Centre d’Etudes du Polymorphism Humain in P aris, It also involved the p articipation of rese archers from a further 19 countries.
Lung cancer is the most common cause of cancer death worldwide with more than 1 million cases diagnosed annually. Before now, no common genetic v ariants that cause the disease had been identified. A two-stage approach was taken to detect DNA v ariants that are related to risk of lung cancer. First, the frequencies of more than 300,000 v ariants covering the whole genome were comp ared in 2000 lung cancer patients and 2500 controls without lung cancer. Then, DNA v ariants that showed m arked differences in frequency were examined in another 2500 patients and 3000 controls to confirm their relationship with disease.
This two-stage approach led to the identification of one genomic region that contains DNA v ariants that are p articul arly common amongst patients comp ared to controls. People who c arry these DNA v ariants in one copy (1 in 2 Europeans) are 30% more likely to develop lung cancer comp ared to those who do not have these v ariants. People who c arry two copies of the v ariants (1 in 10 Europeans) were found to be 80% more likely to develop lung cancer.
The small genomic region in which reside the lung cancer risk v ariants contains several genes that interact with nicotine and other tobacco toxins (nicotinic acetylcholine receptor genes). These genes are widely studied as possible actors in tobacco dependence and the receptors formed by these genes may increase the risk of lung cancer as they are found in the lung and are switched on by nicotine and other c arcinogens found in tobacco smoke.
Over 80% of lung cancer is caused by tobacco smoking – and stopping smoking remains the most important method for preventing the disease. Even among those who quit however, the risk remains high and former smokers make up an increasing proportion of lung cancer patients, especially in countries where tobacco consumption has declined. The DNA v ariants identified in this study increase the risk of developing lung cancer in smokers and former smokers, and they may also increase risk in non-smokers. Present treatment strategies are limited, with only about 15% of patients surviving 5 ye ars. Identifying genes that are involved in lung cancer may therefore suggest treatment t argets or allow for identification of individuals that are at high risk of disease in combination with smoking or other environmental factors.
In addition to providing important insight into the relationship between lung cancer and nicotinic acetylcholine receptors, these findings also represent a powerful demonstration of the ‘genome-wide analysis’ approach to detecting new disease genes. It is likely that as more studies are conducted, and more groups combine their results, further lung cancer genes will be detected using this approach. The study also shows the importance of international collaboration in this new area of scientific rese arch. In order to bring together a study l arge enough to find these genes, studies covering 16 European countries as well as Canada and the US were brought together.
Study author Paul Brennan from the International Agency for Rese arch on Cancer in Lyon said, ‘These results are p articul arly exciting as they provide the first identification of a major genetic factor that contributes to lung cancer risk. These findings will help us understand why lung cancer develops, and may indicate new strategies for treating the disease. They should not however detract from the main lung cancer message that people who smoke should quit. Even those who do not have any copies of the risk gene have an important risk of developing lung cancer, as well as other tobacco related diseases’.
Author, M ark Lathrop, Director of the Centre d’Etudes du Polymorphism Humain and the Centre National de Genotypage, said that ‘the biological mechanism by which these DNA v ariants affect the risk of lung cancer remains to be fully elucidated. C arcinogens may facilitate neoplastic transformation by stimulating angiogenesis and tumour growth mediated through their interaction with nicotinic acetylcholine receptors. The expression of these receptors can also be inhibited by nicotine receptor antagonists. If this mechanism is confirmed, it would most likely open new chemoprevention opportunities for lung cancer’.
Note to editors –
*”A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25” Rayjean J Hung et al. April 3rd 2008. Nature.
Contact: Paul Brennan, brennan@iarc.fr
Tel: +33 472738391
Genetic Epidemiology Group
International Agency for Rese arch on Cancer
150 cours Albert Thomas
Lyon 69008
The International Agency for Rese arch on Cancer (www.iarc.fr)
The International Agency for Rese arch on Cancer (IARC) is p art of the World Health Organization. IARC's mission is to coordinate and conduct rese arch on the causes of human cancer, the mechanisms of c arcinogenesis, and to develop scientific strategies for cancer control. The Genetic Epidemiology Group within IARC conducts l arge scale case–control studies of specific cancers, and p articipates in international consortia, in order to ensure that studies have adequate sample size.
