The Digest

What is the role of ‘chance’ in the risk of cancer?

Judging by the response in the popular press and on social media, Cristian Tomasetti and Bert Vogelstein really have thrown the cat amongst the pigeons with the recent publication of their article, ‘Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions’ in the prestigious scientific journal, Science (1).

Much of the debate (and downright sensationalism!) around this paper has centred on what it can actually tell us about the role of ‘bad luck’ in the onset of cancer. However you look at it, though, there is no doubting the significance of Tomasetti and Vogelstein’s findings. Whilst even the experts appear to disagree on the interpretation of these findings, I think very few would advocate the wholesale dismissal of the role of lifestyle in cancer risk. Indeed, it would be very unwise of an individual to abandon a ‘healthy lifestyle’ in the belief that to do so would have little impact on their risk of cancer.

In this short article, written for the non-expert, I offer my evaluation of Tomasetti and Vogelstein’s findings. Readers with a biomedical background may wish to read the ‘comment’ I have posted on PubMed Commons.

To what extent is cancer down to bad luck?

Scientists often categorise the factors which increase the risk of a particular disease into environmental and genetic factors. The former include diet, smoking, infection and exposure to radiation (including sunlight), as well as various environmental pollutants and industrial chemicals – basically, anything to do with lifestyle, including one’s level of physical activity and weight. The genetic factors are those which we inherit.

Often, the distinction between environmental and genetic causes is clear-cut. Type 1 diabetes, for example, is caused by a genetic fault. Type 2 diabetes, on the other hand, whilst also having definite genetic elements, is linked strongly to lifestyle (especially obesity and lack of physical activity); some people are simply more prone to the type 2 condition – giving them all the more reason to lead a healthy lifestyle! Similarly, whereas there are (relatively rare) genetic conditions which mean an individual will almost certainly develop cardiovascular problems, including heart disease and stroke, these conditions are, in most of us, caused primarily by environmental factors.

It has long been recognised that, no matter how ‘healthy’ a person’s lifestyle, there is an element of bad luck in whether they develop cancer: they may, for example, be unlucky enough to become infected by a tumour virus, or just happen to inhale the ‘wrong’ lungful of air in a busy town where congested vehicles are filling the air with diesel particulates. Even following exposure to a cancer-causing chemical, there is still an element of ‘bad luck’ in whether the individual actually develops the condition – indeed, there always seems to be a ‘bar-room expert’ ready to fill us in with the anecdote of the uncle who lived to be 90, despite smoking every day of his life from the age of seven.

From the outset, then, let me make it clear that, although there is much we can do as individuals to minimise our risk of cancer, lifestyle choices have a far greater impact on one’s risk of developing type 2 diabetes and cardiovascular disease. My doctor informed me, recently, that I have a 3.1 % risk of suffering cardiovascular disease in the next 10 years, clean-living soul that am. (I have this in writing, so may yet hold him to it!) This prediction was based on the outcome of a lifestyle questionnaire, my body-mass index (BMI), blood pressure and various blood tests. He would not be able to offer any such reassurance concerning my risk of cancer: there really is a significant element of bad luck.

The onset of cancer is believed to begin with damage to the DNA in a single cell (the tiny building blocks of which living organisms are composed). DNA is rather like a set of instructions which control all the activities of the cell. Damage to these instructions in a region which controls the growth and development of the cell can lead to cancer, the cardinal feature of which is the development of a mass of such cells (a tumour), which no longer acts in the interests of the body as a whole: rather, it grows uncontrollably, invading and damaging other parts of the body in the process. Consider a cell in your liver: it has particular functions to carry out to the wider benefit of your body, to which it restricts itself. Cancer cells act autonomously, eventually destroying their ‘host’ in the process.

Many chemicals and other environmental agents can damage DNA; they are called mutagens. However, no matter how careful we are to avoid exposure to potential mutagens, a certain amount of DNA damage occurs spontaneously. This is because, when a cell in the body divides, its DNA must be copied. Errors in DNA replication can result in mutations (‘faulty instructions’), just as they can be brought about by external (environmental) factors.

The gist of Tomasetti and Vogelstein’s findings is that, if you compare the number of times the cells in a particular part of the body divide over a lifetime, this correlates very strongly with the incidence of cancer in that part of the body. Thus, they would argue, the rate of cell division in the colon is very high compared with that in the leg. More cell divisions means more ‘chance’ mutations – those that can occur every time a cell replicates its DNA – which accounts for the greater incidence of cancer in the colon than in the leg.

Tomasetti and Vogelstein made such comparisons involving cancers in numerous parts of the body: the ‘connection’ they found between the incidence of cancer and the number of cell divisions in a particular tissue was so strong, it led them to conclude that these chance (spontaneous) mutations play a greater role than environmental factors in the onset – and, hence, risk – of cancer. Powerful though the statistical relationship revealed by Tomasetti and Vogelstein may be, I make the case (in my PubMed Commons post) that there is an alternative explanation for this observation, which I also describe briefly below.

I mentioned above that a mutagen need damage the DNA in only a single cell for a tumour to arise. The faulty cell must undergo many cycles of cell division to become the mass of faulty cells that form the tumour. Cell division is, therefore, a key stage in the development of cancer. Indeed, it is believed that the DNA in a very large number of cells in the human body is damaged on a daily basis by exposure to mutagens, including the free radicals generated in cells from the oxygen we must breathe.

Fortunately for us, most of the cells damaged in this way never develop into cancers. This is because sophisticated damage surveillance and detection systems protect us from cancer: damaged DNA can be detected and repaired; faulty (precancerous) cells can be identified and eliminated (e.g. by the immune system). Once the DNA in a particular cell has been damaged, a race is on: can the cell be repaired or removed before it divides? If the mutation occurs in a cell type having a high rate of cell division, it is more likely to lead to a colony of modified cells and, consequently, a tumour.

Such a view of the origins of cancer is consistent with the statistical trend reported by Tomasetti and Vogelstein: an environmental ‘factor’ – such as a mutagen from burnt meat or another harmful chemical – acting on a cell in, for example, the colon is more likely to result in a tumour than a mutagen acting on a cell in the leg. The relationship (correlation) between the rate of cell division and the risk of cancer is so convincing because, cell division is needed to ‘translate’ a mutation caused by an environmental agent into a tumour, which must occur before the mutated cell is repaired or deleted by the various surveillance systems in the body.

No multi-stage process can proceed faster than its slowest step (chemists call this the 'rate-limiting step'). If I were foolhardy enough to set off in my car and head for Central London, my total journey time would be determined not so much by how fast I hurtled down the M40, but by the ease with which I managed to negotiate the congested roads and streets within the M25. Similarly, no matter how many environmental mutagens you throw at the DNA of a cell, its rate of conversion to a tumour is determined by the rate-limiting step of the whole process – the rate of cell proliferation.

If this is the case, then environmental factors may play a greater (albeit ‘hidden’) role in the risk of cancer than might be suggested by Tomasetti and Vogelstein. It could be argued that the environmental component of cancer risk has evaded detection by the statistician’s radar.


  1. Tomasetti, C. and Vogelstein, B. (2015) Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347 , 78 - 81. doi: 10.1126/science.1260825 [Abstract and PubMed Commons]

Mark Burkitt

Westcott Research and Consulting

Article published 15 January 2015

If you would like to learn more about the role of diet in health and disease (including heart disease and cancer), it is recommended you read Dr Burkitt’s book, Healthy Eating through informed Choice (Troubador Publishing, 2014, ISBN: 9781783064793).

Whilst the book is written in non-technical language and is intended primarily for readers with absolutely no background in science, it is hoped that trained scientists and health professionals will also find the material to be of interest. The book is extensive in its scope and challenges some of the conventional views on the role of diet in human disease, questioning – in particular – the wisdom of the mainstream advice to consume a diet high in polyunsaturated vegetable oils. It is explained how the high susceptibility of polyunsaturates to damage by free radicals means they, rather than saturated fats, are likely to be a major cause of human disease.

Dr Burkitt's book is available for purchase from [Troubador Publishing], [Amazon], [WHSmith], [Blackwell's] and all other good book shops.

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