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Beyond the luck of the draw

Dr. Arunabha Sengupta.

The Telegraph, 03 March 2015

 
Recently, a paper on the causes of human cancers in Science, January 2, 2015, by Cristian Tomasetti with Bert Vogelstein of Johns Hopkins Hospital, captured wide media attention, only to be followed by an immediate backlash from a riled science community. The bane was media's highlighting of the researchers' pronouncement that two-thirds of all cancers are due to just plain bad luck and are not caused by lifestyle or environmental factors. But for the two phrases, 'bad luck' and 'two-thirds of all cancers', this paper, a statistical totting up of numbers of stem cell divisions in different tissues with their lifetime risk for cancer, would have been deemed by the majority as an addition to the known design of carcinogenesis. That is, to develop a cancer there has to be a build up of mutations or wrong structuring of replicating DNA during cell divisions, and, as stem cells in different tissue types divide at different rates, faster dividing types have greater probabilities of developing mutant cells and subsequently cancers.

Those two phrases created media sensation, confused the public, and threatened to derail cancer control campaigns by describing 'bad luck' as the cause of random accidental mutations during cell division without any external cause in two-thirds of all cancer cases. Scientists responded with alacrity and got down to do a closer scrutiny of the paper which revealed that the authors have selected 31 cancer types based not on their importance but simply because their stem cell division numbers could be obtained or assumed from available literature. So their list includes some rare cancers but omits common cancers like breast, prostate, cervix, epithelial ovarian cancers, stomach, urinary bladder and so on. Moreover, the study was limited to only the American population while the inclusion of other geographic regions could have derived different figures, as was pointed out by the International Agency for Research on Cancer.

Through a press release (Lyon, January 13), the IARC pointed out how environmental factors can alter cancer patterns, for example, oesophageal cancer is common among men in East Africa but rare in West Africa, and how patterns can also vary over time, for example, colorectal cancer, once rare in Japan has now increased four-fold in the last two decades. Based on solid epidemiological and molecular research, the IARC declared that environmental and lifestyle exposures influence 50 per cent of world incidence of common cancers. Cancer Research UK puts that figure at 40 per cent. Statisticians accused the authors of 'over interpreting' their data and pointed to irregularities in the methodology used. It baffled clinicians that separate data sets were used for smokers and non-smokers in lung cancer, and that osteosarcoma was split into five tissue types based on locations.

The criticism compelled journalists to re-engage, the Johns Hopkins to issue clarifications, and the authors to promise further technical reports. It now appears that they never meant to say, "two thirds of all cancer cases". What they said was that two-thirds of the variation in cancer rates between studied tissue types can be explained by stem cell divisions ( rates of), and as the somatic mutations that arise during these divisions are stochastic, they happen just by chance. Jennifer Couzin-Frankel, the news writer of Science, wrote, "Immediately, I knew that I had written part of that sloppily." She went back to the authors. "It was only after more hours spent on interviews that I finally understood the two-thirds figure. Some tissues are overtaken by cancer more readily than others, and mutations accumulating in stem cells explained two-thirds of that variability."

In the Johns Hopkins clarification of January 7, to explain their proposition that only the number of stem cell divisions correlate with the incidence of cancer in most cases, the authors drew an analogy with car driving where, they say, only distance or number of miles (or number of stem cell divisions) correlates with number of accidents (mutations) irrespective of the conditions of the road (life style and environmental factors) or of the car (inherited factors). Because if distance is zero, there will be no accident. Their reasoning may apply to population groups but says nothing about individual risks. Are all drivers who meet with accidents just unlucky or some pre-select themselves with poor skill and hasty driving? Interestingly the authors then added, "We emphasize that no single factor causes cancer. Some have misunderstood our research to say that two-thirds of all cancer cases are due to bad luck. We want to stress that cancer is caused by a combination of many factors. Referring back to our car analogy, we can't say that two-thirds of accidents are caused solely by the length of the trip. Every accident is caused by some combination of road conditions, car conditions, length of the trip and other factors."

The writers, however, laid greater stress on secondary prevention of cancer by early detection over primary prevention through awareness which, the IARC warned, "If misinterpreted, this position could have serious negative consequences from both cancer research and public health perspectives."

After deducting the hype over misinterpretation and some inherent flaws of the methodology, this paper does not tell us much beyond what we know, that carcinogenesis is an unpredictable multi-step process initiated by mutations caused by a combination of known and unknown factors. But it certainly brings up that provocative question, can science accommodate such thoughts as attributing the unknown to the 'magic hands of chance'?