Source: Johns Hopkins Medicine. Credit: C Tomasetti, B Vogelstein and Illustrator Elizabeth Cook, Johns Hopkins.
Researchers at the Johns Hopkins Kimmel Cancer Center have discovered that about two-thirds of adult cancers can be attributed to random genetic mutations, while the remaining third stem from environmental and hereditary factors. Published in Science, the paper, titled Variation in cancer risk among tissues can be explained by the number of stem cell divisions, emphasizes that this doesn’t mean two-thirds of all cancers are solely due to chance, as the impact of chance varies between cancer types.
To illustrate this concept, Drs. Bert Vogelstein and Cristian Tomasetti from Johns Hopkins use the analogy of a car accident. They explain that developing cancer is like being in a car accident, where the length of the trip correlates with the risk of an accident.
In this analogy, road conditions represent environmental factors influencing cancer risk, while the car’s condition symbolizes inherited genetic factors. Just as poor road conditions and a faulty car increase accident risk, so do environmental hazards and inherited genetic mutations increase cancer risk.
The length of the trip represents the process of stem cell division and random mutations. Regardless of road conditions or the car’s state, a longer trip inherently carries a higher accident risk. Similarly, the likelihood of developing cancer increases with the accumulation of random mutations during stem cell divisions throughout one’s life.
Applying this analogy, approximately two-thirds of the accident risk can be attributed to the trip’s length, with the rest stemming from factors like poor car condition and hazardous roads. This translates to roughly two-thirds of cancer risk being linked to random mutations during stem cell divisions, while the remaining risk is associated with environmental and hereditary factors.
“People who live long lives despite exposure to cancer-causing agents, like tobacco, are often said to have ‘good genes,’ but the reality is that many of them were just lucky,” Dr. Vogelstein remarked in the initial January 1 statement.
Drs. Tomasetti and Vogelstein arrived at their conclusions by examining scientific literature to determine the total number of stem cell divisions within 31 tissue types during an average person’s lifespan. They focused on stem cells because these cells replenish dying cells within specific organs through a “self-renewal” process.
Vogelstein points out that it’s already established that cancer develops when errors, or mutations, occur during stem cell division. These mutations involve the incorrect swapping of chemical letters in DNA during replication. The higher the number of mutations, the greater the risk of uncontrolled cell growth, a defining characteristic of cancer.
The scientists mapped the frequency of stem cell division in 31 different body tissues and compared this data with the lifetime cancer risks for those same tissues within the American population. Their findings revealed a correlation of 0.804 between the total number of stem cell divisions and cancer risk. In mathematical terms, a value closer to one indicates a stronger correlation, suggesting a probable, though not definitively causal, relationship between the two factors.
“Broadly, our study demonstrates a strong correlation between changes in the number of stem cell divisions within a tissue type and changes in cancer incidence within that same tissue,” explains Vogelstein. He cites colon tissue as an example, which undergoes four times more stem cell divisions than small intestine tissue in humans, resulting in a significantly higher prevalence of colon cancer compared to small intestinal cancer.
To delve further into this correlation and explore a causal link, the researchers sought to validate the relationship between stem cell division and cancer development. “One might propose that the colon’s exposure to more environmental factors than the small intestine contributes to a higher potential for acquired mutations,” Tomasetti suggests.
However, the scientists observed a contrasting pattern in mouse colons. Mice exhibited fewer stem cell divisions in their colons compared to their small intestines, and, interestingly, they also had a lower incidence of colon cancer compared to small intestinal cancer. This finding supports the idea that the overall number of stem cell divisions plays a more significant role in cancer development than factors specific to the colon itself.
The research duo categorized the cancer types they studied into two groups. Through statistical analysis, they determined which cancers had an incidence rate predictable by the number of stem cell divisions and which ones had a higher incidence than expected. Their analysis revealed that 22 cancer types could be primarily attributed to the “bad luck” factor of random DNA mutations occurring during cell division. The remaining nine cancer types displayed incidence rates exceeding those predicted by chance alone, implying a combined influence of “bad luck” and environmental or hereditary factors.
“We observed that the cancer types exceeding the risk predicted by stem cell division numbers were precisely those expected, including lung cancer linked to smoking; skin cancer associated with sun exposure; and cancer types linked to hereditary syndromes,” reports Vogelstein.
“This study emphasizes that lifestyle choices, such as smoking, can compound cancer risk. However, many cancers arise predominantly from the unfortunate occurrence of mutations in cancer-driving genes, irrespective of lifestyle or hereditary factors. Early detection, when these cancers are still treatable with surgery, remains the most effective way to eliminate them,” Vogelstein adds.
Both scientists predict a future increase in cancer cases simply due to the correlation between aging and increased stem cell divisions. “Research on primary and secondary prevention, cancer treatment, and the fundamental biology of the disease is more critical than ever,” they emphasize in the FAQ.
The study can be found in Science here_. The FAQ is available here.
*The scientists acknowledge that certain cancers, such as breast and prostate cancer, were excluded from the report due to the lack of reliable stem cell division rates in existing scientific literature. They encourage other researchers to contribute to refining their statistical model by uncovering more precise stem cell division rates.
Funding for this research was provided by the Virginia and D. K. Ludwig Fund for Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, and the National Institutes of Health’s National Cancer Institute (grants P30-CA006973, R37-CA43460, RO1-CA57345 and P50-CA62924).