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Study featuring genomic sequencing & international data shows random errors...

American Association for the Advancement of Science

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IMAGE: This image depicts the mutations attributable to environmental factors (right), DNA replication (center) and heredity (left) in the UK female population. This material relates to a paper that appeared in... view more

Credit: C. Tomasetti et al,. Science (2017)

The mutations that cause human cancer have traditionally been thought to originate from two main sources -- heredity and environment -- but now, new work by researchers including Cristian Tomasetti and Bert Vogelstein emphasizes the importance of a third source of these mutations. The researchers analyzed genome sequencing and epidemiologic data from 32 cancer types and concluded that nearly two-thirds of mutations in these cancers are attributable to random errors that occur naturally in healthy, dividing cells during DNA replication. Their analysis further supports the role for mutations caused by random DNA copying errors in driving cancer, the researchers say. What's more, their approach for determining the proportion of cancer mutations that result from replication errors, versus inherited or environmental factors, offers a novel perspective on cancer development.

In a second analysis including data from 69 countries spanning 6 continents, Tomasetti and Vogelstein found that the high correlation between cancer incidence and the total number of divisions of normal stem cells they had previously reported in 2015, albeit from a U.S.-only population, persisted. This was true across countries with widely different environments. To make this assessment, Tomasetti and Vogelstein leveraged 423 international cancer databases, analyzing published data on stem cell divisions in different human tissues and comparing the data to the lifetime incidence of 17 cancer types. The data revealed a strong correlation between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. Critically, the findings underscore the need for more research efforts focused on secondary prevention (early detection and early intervention); indeed, for cancers in which all mutations are the result of random mutations, secondary prevention may be the only option, the researchers say. Meanwhile, for cancers in which only a small percentage of mutations are due to random DNA replication errors, primary prevention (that aimed at minimizing harmful environmental exposures) will continue to be the most effective way to reduce cancer deaths. Tomasetti and Vogelstein emphasize that the results of their study are fully consistent with epidemiologic evidence on the fraction of cancers in developed countries that are potentially preventable through improvements in environment and lifestyle. Cancer Research UK, for example, estimates that 42% of cancer cases are preventable, while the U.S. Centers for Disease Control and Prevention estimates that 21% of annual cancer deaths can be prevented. A Perspective by Martin Nowak and Bartlomiej Waclaw discusses the 2015 and 2017 Science papers in greater detail.

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