By a Medical Student at Cambridge
Risk factors for lung cancer:
The International Agency for Research on Cancer and the World Cancer Research Fund/American Institute for Research have found over 40 risk factors for lung cancer [1]. In this section, we will look at three of the most important risk factors for lung cancer: tobacco smoking, ionising radiation and asbestos exposure.
2.1. Smoking Smoking is the leading cause of lung cancer, not just in the UK, but worldwide. When interviewing Dr Maggie Harris, a Clinical Oncologist at the Christie who specialises in lung cancer, she informed me that around 90% of her patients diagnosed with lung cancer are smokers.
Government efforts to raise awareness about the dangers of smoking, including the complete banning of TV advertising in 1991 [2], the banning of smoking in public places in 2004 [3] and the introduction of warning labels on tobacco packaging have all helped to reduce the smoking rates in the UK, but the number of deaths due to lung cancer remains very high. To understand why, we must look at some epidemiological data examining the link between smoking and death due to lung cancer. The graphs below show the number of deaths from lung cancer in the UK correlated to cigarettes smoked per year (1910 – 1990) [4]:
From these graphs, we can see there is a very strong association between the number of cigarettes smoked and deaths per year. It is interesting to note that there is an approximate 20 - 30 year delay between the association (i.e. when the number of cigarettes smoked per person per year increases, the number of deaths per year due to lung cancer increases approximately 20 - 30 years later (and vice versa)).
This is because lung cancers typically have a time lag of more than 20 years between exposure to carcinogens (in cigarette smoke) to the onset of symptoms [5].
This is a very important fact and it is, perhaps, the main reason why lung cancer is such a common cause of death in the UK in the present day – 30 years ago, the average number of cigarettes smoked per person per year was very high (looking at the graph it was around 22000) and so, now, in the present day, due to the time lag between exposure and onset of symptoms, the number of deaths from lung cancer is very high. It will be a while before the number of deaths from lung cancer falls to reasonable numbers due to this time lag but, as smoking rates continue to fall in the UK, we can expect deaths due to lung cancer to fall accordingly in years to come.
How does smoking cause lung cancer?
So far, 81 chemical carcinogens have been identified in cigarette smoke [6]. Carcinogens are substances that can damage the genome, sometimes causing mutations in important genes (proto-oncogenes or tumour suppressor genes) which results in unregulated cell growth. This can eventually lead to cancer. Below is an example of how a carcinogen can cause cancer: Benzo[a]pyrene, a procarcinogen present in cigarette smoke, is metabolised in the body to the mutagen benzo[a]pyrene diol epoxide. There are indications that this molecule targets the p53 gene (an important tumour suppressor gene) and binds to certain bases along the gene, forming DNA adducts [7]. These DNA adducts mask the genetic code so that, when the next cycle of cell division comes along, DNA polymerase misreads the bases with DNA adducts and inserts an incorrect base in the new strand. For example, if one of the bases on the original strand was a ‘G’ but benzo[a]pyrene diol epoxide has bound to this guanine, DNA Polymerase may interpret the ‘G’ as a ‘T’ resulting in an ‘A’ being inserted into the corresponding place on the new strand, leading to a G to T transversion mutation. Such G to T transversions are common with smoking associated lung cancers [8].
The mutations to the DNA of the p53 gene may lead to inactivation of its tumour suppressing ability in certain cells, leading to cancer.
2.2. Ionising Radiation
Radon is a colourless, odourless and radioactive gas that can be inhaled into the lungs. It decays into solid radioactive elements called radon progeny. These progeny can attach to dust and other particles in the air and then be breathed in. [9]
Once inhaled, radon and radon progeny decay, releasing alpha particles, a form of ionising radiation, which are absorbed by the nearby lung tissue; causing damage which can lead to cancer. [10] Approximately 0.5% of lung cancer cases in the UK are linked to exposure to residential radon alone (exposure at home as opposed to occupational exposure), but 3.4% of lung cancer cases are linked to radon and smoking in combination (in the sense that lung cancer could have been avoided by avoiding either exposure).
Every building contains traces of radon but chances of a high level of radon usually depends on the type of ground in the area. The maps below show the percentage of homes in the UK that are at or above the action level (200 Bq m-3). [11]
A pooled analysis showed that the risk of getting lung cancer increases by 16% for every 100 Bq m-3 increase in usual home radon level27, with the average UK home radon concentration level being 20 Bq m-3.28 So, looking at the maps on the previous page, we can see that, in a significant portion of England and Wales and in a fraction of Scotland and Northern Ireland, more than 30% of houses have radon levels greater than or equal to 200 Bq m-3. In fact, the Health Protection Agency, based on 480,000 radon measurements, estimated that between 100,000 and 200,000 homes in England and Wales have radon levels greater than the action level (200 Bq m-3).
This large number of homes is one of the reasons why lung cancer is such a common cause of death in the UK; radon levels in many homes across the UK are far above the safe level, leading to an increase in the incidence of lung cancer, leading to an increase in lung cancer mortality.
There are many relatively cheap ways of reducing the radon levels in one’s home; an example being the use of a radon sump. Therefore, in order to reduce lung cancer mortality due to radon exposure, home owners living in a radon affected area need to ensure they have had a home radon measurement taken and, if the level is found to be above 100 Bq m-3, they need to ensure appropriate action is taken to reduce the radon levels. How does ionising radiation cause lung cancer?
Ionising radiation includes alpha particles, beta particles and gamma rays. When these strike molecules in its path, electrons may be displaced from atoms within the molecule. The loss of electron(s) converts the molecule into an ion (charged molecule).
Ionising radiation can damage DNA directly by ionising the atoms comprising DNA, or indirectly by interacting with water molecules (radiolysis) to generate dangerous intermediates known as reactive oxygen species (ROS) which can oxidise DNA.
Thus, by either method (direct ionisation/generation of ROS), DNA can become oxidised. Oxidation of DNA bases can lead to DNA Polymerase misreading the base and inserting an incorrect base in the new strand. For example, a guanine base could become oxidised to 8-oxoguanine and DNA Polymerase would mispair 8-oxoguanine with adenine during DNA replication, leading to a G to T transversion mutation.
If many mutations occurred in proto-oncogene(s) or tumour suppressor gene(s) then unregulated cell growth may result, leading to cancer.
2.3. Asbestos Exposure
Asbestos is a group of fibrous silicate minerals that was used extensively in building/electrical insulation but is now prohibited from being used in many countries across the world because of its association with several diseases of the lung, including lung cancer and mesothelioma. [11]
It is estimated that up to 8% of lung cancers in the UK each year are caused by asbestos exposure.[12] This means that in 2012, around 2000 lung cancer deaths were due to asbestos exposure. It is also interesting to note that smoking and asbestos exposure, much like smoking and radon exposure, have a synergistic effect on lung cancer development.[13]
Asbestos exposure in the UK mainly came through occupational exposures (construction and shipyard workers were commonly exposed to asbestos [14] ), and exposure has been estimated to have peaked in 1963.[15]
So, why is asbestos still causing people to die from lung cancer (and mesothelioma) more than 50 years after exposure levels supposedly peaked? The answer lies in the fact that asbestos-related diseases have a long latency period from the time of initial exposure to the development of a disease.
Asbestos-related lung cancer has a latency period of around 15-35 years [16] and since the use, import and sale of asbestos was only fully banned in 1999 (blue and brown asbestos materials were banned in 1985 and white asbestos was banned in 1999) [17], we can understand why so many lung cancer deaths in the present day are due to asbestos exposure: people who were exposed to asbestos in the early 1980s are only now, 30 years later, developing symptoms of lung cancer and, unfortunately, many of these people will go on to die from the disease.
Therefore, I can say that asbestos exposure in the late 20th Century is one of the reasons why lung cancer is such a common cause of death in the UK. Many people have died from exposure and, unfortunately, many will die in the future, but the good news is that mortality is expected to peak in 2016 with a rapid decline thereafter [18]; meaning that asbestos-related lung cancer will eventually be a thing of the past in the UK. However, in the developing world, particularly in India, asbestos use is increasing exponentially with few, if any, precautions being taken. [19] Therefore, asbestos-related lung cancers are likely to increase dramatically in the developing world.
How does asbestos cause lung cancer?
Asbestos fibres, typically of length 5mm, tend to lodge in lung tissue and they can cause cancer in a number of ways.
Asbestos induces cell necrosis which causes the release of the HMGB1 protein. This protein is a key mediator of inflammation. The resulting inflammatory response consists largely of phagocytic macrophages which release numerous cytokines and mutagenic ROS.[20] One such cytokine is tumour necrosis factor-α (TNF-α). This activates the transcription factor NF-κβ. NF-κβ has many effects that contribute to tumorigenesis, such as the inhibition of apoptosis and the promotion of metastasis and angiogenesis.[21] In addition to TNF-α, another cytokine produced by the macrophages, IL-1β, has also been shown to be linked to asbestos-related carcinogenesis. The mutagenic ROS produced by the macrophages, as we already know, can mutate DNA in proto- oncogenes and tumour suppressor genes, leading to unregulated cell growth, which can lead to cancer. Thus, the cytokines and ROS released by macrophages in the inflammatory response can cause asbestos-related lung cancer and mesothelioma. HMGB1, TNF-α, IL-1β and other proteins are being investigated as possible therapeutic targets as the inhibition of these proteins would likely prove effective in preventing asbestos-related carcinogenesis.[22] It has also been speculated that DNA damage can be caused by asbestos fibres interfering with chromosome segregation during mitosis, leading to chromosomal aberrations which can lead to cancer.[23] To summarise this section then, I can say that lung cancer is such a common cause of death in the UK partly due to the mistakes of the past: the time lag between exposure to cigarette smoke/asbestos and the onset of symptoms of lung cancer means that due to the high levels of exposure in the past, we are suffering in the present. However, the future is bright when looking at these risk factors because smoking rates are falling significantly and asbestos exposure has been significantly reduced; meaning there will be fewer deaths from these causes in the future. Lung cancer is also a common cause of death because of large areas in the UK being radon affected; thousands of homes are exposed to high levels of ionising radiation. However, with further education, more at risk homes will have remedial work done that will decrease radiation levels to the normal range.
The sheer number of risk factors can also be regarded as a reason for the high mortality of lung cancer, although it should be noted that the risk factors covered in this section comprise the vast majority of the causes of lung cancer with other risk factors such as arsenic exposure, air pollution etc. accounting for a very small percentage of lung cancer cases [24], but these other risk factors nevertheless contribute to the number of lung cancer-related deaths. Further Reading:
1. (2013). Lung cancer risk factors. Available: http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/riskfactors/lung-cancer-risk-factors#source22. Last accessed 21st August 2014. 2. Jenkins, S. (2006). Cigars, cigarettes and tobacco. Available: http://www.headington.org.uk/adverts/cigars_cigarettes_tobacco.htm. Last accessed 21st August 2014. 3. (2004). Smoking ban proposed for England. Available: http://news.bbc.co.uk/1/hi/health/4014597.stm. Last accessed 21st August 2014. 4. Toole, G and Toole, S. (2008). Causes of disease. In: AS AQA Biology. London: Nelson Thornes. p10.
5. Proctor, R. (2001). Tobacco and the global lung cancer epidemic. Nature Reviews. 1, p82-86. 6. Pecorino, L. (2012). Introduction. In: Molecular Biology of Cancer. 3rd ed. Oxford: Oxford University Press. p12. 7. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. (2002). Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 8. (48), p7435-7451. 20 ibid 9. (2013). Radon. Available: http://www.cancer.org/cancer/cancercauses/othercarcinogens/pollution/radon. Last accessed 21st August 2014. 10. (2009). What is radon?. Available: http://www.ukradon.org/information/whatisradon. Last accessed 21st August 2014.
11. Pecorino, L (2012). Molecular Biology of Cancer. 3rd ed. Oxford: Oxford University Press. p35 12. McCormack V, Peto J, Byrnes G, Straif K, Boffetta P. (2012). Estimating the asbestos-related lung cancer burden from mesothelioma mortality. British Journal of Cancer. 106 (3), p575-584. 13. Erren TC, Jacobsen M, Piekarski C. (1999). Synergy between asbestos and smoking on lung cancer risks. Epidemiology. 10 (4), p405-411 14. Rake, C et al. (2009). Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. British Journal of Cancer. 100 (7), p1175-1183. 15. Tan, E et al. (2010). Projection of mesothelioma mortality in Britain using Bayesian methods. British Journal of Cancer. 103 (3), p430-436. 16. (2014). Asbestos Lung Cancer. Available: http://www.asbestos.com/cancer/lung-cancer/. Last accessed 24th August 2014. 17. (2014). Asbestos. Available: http://en.wikipedia.org/wiki/Asbestos#1960s.E2.80.931980s. Last accessed 24th August 2014 18. Tan, E et al. (2010). Projection of mesothelioma mortality in Britain using Bayesian methods. British Journal of Cancer. 103 (3), p430-436 19. Burki T. (2010). Health experts concerned over India's asbestos industry. The Lancet. 375 (9715), p626-627.
20. Carbone M, Yang H. (2012). Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clinical Cancer Research. 18 (3), p598-604 21. Pecorino, L (2012). Molecular Biology of Cancer. 3rd ed. Oxford: Oxford University Press. p238-239 22. Carbone M, Yang H. (2012). Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clinical Cancer Research. 18 (3), p598-604 23. Olofsson K, Mark J. (1989). Specificity of asbestos-induced chromosomal aberrations in short-term cultured human mesothelial cells. Cancer Genetics and Cytogenetics. 41 (1), p33-39. 24. (2014). Lung cancer risk factors. Available: http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/riskfactors/lung-cancer-risk-factors. Last accessed 24th August 2014.