Over 60% of cancer-producing mutations are caused by genetical ‘typos’, errors that occur in DNA copying inside cells, a new paper suggests.

Metastatic Melanoma Cells.
Image credits National Cancer Institute.

The main implication of this finding is that cancer mutations aren’t caused by heredity or other environmental or intrinsic factors as often as we believed. In short, simple bad luck may play a much bigger hand in the development of cancer than we’d like to believe. This could change how researchers think about fighting the disease, says study co-author Bert Vogelstein, a geneticist at the Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who believes that we’ve placed too much importance on environmental factors up to now. Early detection and treatment should be prioritized in addition to prevention, he adds.

“If we think of the mutations as the enemies, and all the enemies are outside of our border, it’s obvious how to keep them from getting inside,” Vogelstein explains.

“But if a lot of the enemies — in this case close to two-thirds — are actually inside our borders, it means we need a completely different strategy.”

Ctrl-c, Ctrl-typo

When cells divide, they need to copy (replicate) their DNA so that both cells gets its own copy. This process creates an opportunity for errors to creep up into the genome since replication relies on physically disassembling the DNA then stitching the copy together one nucleotide at a time.

Two years ago Vogelstein and one of his co-authors, mathematician Cristian Tomasetti of Johns Hopkins University in Baltimore published the results of an analysis which aimed at understanding why some cancer types occur more often than others. Areas with lower stem cell division rates, such as the brain, were found to associate with less common incidence of cancer and areas with high rates were associated with more common types, such as colorectal cancer. They concluded that stem cell division rates in an organ correlated to the frequency with which cancers developed in the area.

It sparked a whole controversy, mainly because scientists were worried people would understand that prevention is useless — which is not true. Vogelstein himself said that the study never aimed at challenging prevention efforts for known causes of cancer, such as excessive sun exposure or smoking, which both foster mutations. He adds that about 42% of cancers are preventable according to epidemiological studies, and his results don’t contradict that finding — because his work looks at the number of cancer-causing mutations, which typically need to add up to create the disease, the numbers aren’t “directly comparable,” he explains.

This latest study comes to address two of the main criticisms brought against the 2015 paper. First of all it expanded the analysis beyond the US by drawing on records of cancer incidence from 69 different countries and looked at two common cancer types — prostate and breast — which weren’t included in the first study.

The faults in our genes

Breast cancer cell.
Image credits National Cancer Institute.

To find which mutations were linked to particular environmental exposures, the team used data from an UK cancer database and cancer genome sequencing efforts. They then used the data to calculate the relative contribution of environmental and hereditary functions, as well as that of random replication errors in the incidence of cancer-causing mutations.

These percentages varied from cancer to cancer. For some lung tumors, for example, environmental factors caused 65% of all cancer-causing mutations, and replication errors accounted for only 35%. In prostate, brain, and bone cancers, however, DNA-replication errors accounted for 95% of this number. Averaged across 32 types of cancer, about 66% of cancer-driving mutations originated in replication errors, 29% in environmental factors and 5% in inherited mutations.

Overall, calculations across 32 cancers indicated that about 66% of cancer-driving mutations are due to random DNA replication errors, with only 29% due to environmental factors and 5% to inherited mutations.

The paper did raise criticisms of its own, mostly that it underestimates the effect of environmental factors (you can factor in the effect of cigarette smoke, for example, but not that of air pollution in traffic or at work), or about the assumptions the team makes to simplify their analysis. But in this case controversy may have been a boon for cancer patients everywhere — after all, controversy is what made scientists look into the causes of cancer, and this paper is no exception.

Just to be clear, this doesn’t mean that environmental factors and lifestyle choices don’t play a part in cancer development because they certainly do. But sometimes it just comes down to chance. You could be doing everything right, and it will still go wrong. In the end, Vogelstein hopes that his work will help patients and their families — especially parents of children with cancer — to work through the guilt often accompanying the condition.

“They need to understand that these cancers would have occurred no matter what they did,” he says. “We don’t need to add guilt to an already tragic situation.”

The paper “Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention” has been published in the journal Science.