Cancer – luck of the draw

You don’t smoke, you don’t drink, you eat moderately and you exercise 3x a week. What are the chances you’ll still get cancer?

It’s luck of the draw, according to researchers Cristian Tomasetti, Ph.D., and Bert Vogelstein, M.D., both from Johns Hopkins Kimmel Cancer Center. They recently published in Science that majority of cancer mutations are largely attributed to DNA copying errors made during cellular replication (named R in study). The other two driving factors – environment (E) and genetic inheritance (H) – took a backseat in most cancers, with the exception of lung, skin and esophageal cancers.

Their conclusions were based mainly on looking at the correlation between stem cell divisions and cancer incidence. The idea being that the more divisions a cell makes, the greater the occurrence of DNA copying errors. As mutations accumulate, the risk of cancer correspondingly increases.

Looking at 69 countries and 17 different tissue types, they found correlation values ranged between 0.6-0.9. This high correlation was “surprising” as it was expected that the diverse environmental factors in different countries would have dampened the impact of stem cell divisions. They found this correlation increased with greater age range (0-89) although stem cell divisions do not increase proportionally with age in certain tissue types like bone and brain. I do not have access to the supplementary materials but would have liked to see what the correlation values were based on tissue type and different age ranges.

The authors attributed DNA copying error-induced mutations to four sources:    1) mispairing   2) polymerase errors   3) base deamination (i.e. losing of the amine group) and 4) free radical damage (i.e. oxidative stress).

To be honest, the finding is hardly surprising. The accumulation of spontaneous mutations over one’s lifetime is a well-known fact. Cancer occurs when the scales eventually tip – i.e. enough mutations occur such that tumour suppressors are no longer  able to hold oncogenes in check – setting the cell on a path to rapid multiplication and eventual destruction.

What perhaps is controversial is that what people may take away from the finding is that there’s no point in living healthy, we’re all going to die anyway!

Here’s the breakdown of each contributing factor when 32 different cancer types were modeled based on epidemiological findings. Their mathematical model assumed that cancers not induced by environment (E) or inheritance (H) was due to DNA copying errors (R):

“The median proportion of driver gene mutations attributable to E was 23% among all cancer types. The estimate varied considerably: It was greater than 60% in cancers such as those of the lung, esophagus, and skin and 15% or less in cancers such as those of the prostate, brain, and breast. When these data are normalized for the incidence of each of these 32 cancer types in the population, we calculate that 29% of the mutations in cancers occurring in the United Kingdom were attributable to E, 5% of the mutations were attributable to H, and 66% were attributable to R.”

Researchers are chiding the study as being over-simplified and going against previous evidence that 42% of cancers can be prevented by lifestyle and diet changes. The controversy has happened before as a previous study by the same authors essentially demonstrated the same findings but with sampling limited to the US.

However, its not like the authors entirely dismissed environment and genetic inheritance, deeming it unimportant. They obviously can impact outcomes as seen for certain cancers. In addition, they acknowledge certain cancers cannot be explained by DNA copying errors alone and require further epidemiological investigation.

More importantly, is what one can do to counter this source of mutations. The authors call for early diagnosis or introducing “more efficient repair mechanisms”. This can certainly drive efforts towards a new therapeutic approach focusing on DNA repair. With genetic intervention becoming commonplace in the lab and scientists relying on DNA repair mechanisms to introduce artificial mutations, its only a matter of time till we learn how to better write DNA or find ways to correct copying errors. And if this may lead to the cure for cancer then…  that’s one big problem solved!

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