The lifetime risk of many different types of cancer are correlated (0.81) with the total number of divisions of their tissue stem cells, a recent study round.
This can allow any of the most common cancer types to be differentiated into replicative (R) or deterministic (D) types, according to the results of a correlative literature review comparing cancer incidence in tissues to their known stem cell behavior. Whether a cancer is R or D has profound implications for prevention and detection, according to a report in Science (2015;347:78-81).
Extreme variation in the lifetime incidence of cancer across various tissues exist, ranging from levels such as 6.9% in the lung down to 0.00072% for laryngeal cartilage, according to Cristian Tomasetti, Ph.D., of the Johns Hopkins Bloomberg School of Public Heath and Dr. Bert Vogelstein of the Johns Hopkins Kimmel Cancer Center, both in Baltimore.
Environmental exposure to known carcinogens seems to be a factor in some, but this cannot explain why cancers of the small intestinal epithelium are three times less common than brain tumors, even though the intestinal cells are exposed to much higher levels of environmental mutagens than are the brain cells, which are protected by the blood-brain barrier. And heredity fails as a complete explanation, with only 5%-10% of cancers having a heritable component.
“If heredity and environment factors cannot fully explain the differences in organ-specific cancer risk, how else can these differences be explained?” the authors asked. They postulated that somatic cell mutation during DNA replication as the result of cell division may be a critical factor, implying that the greater level of cell division, the greater level of mutagenesis, and hence cancer. Stem cells, which both self-renew and are responsible for tissue maintenance were the obvious candidates for such mutations, and recently the technology has developed to detect and quantify them.
Via a literature search, the authors identified 31 tissue types in which stem cells had been quantitatively assessed, then plotted the total number of stem cell divisions during an average human lifetime for each of these tissues on the X axis, and the lifetime risk in the United States for the associated cancer types from sources such as the Surveillance, Epidemiology, and End Results (SEER) database. Not only was there a strikingly high positive correlation (0.81), which indicated that 65% of the differences of cancer risk among different tissues can be explained by the total number of stem cell divisions in these tissues, the correlation extended across five orders of magnitude, “thereby applying to cancers with enormous differences in incidence,” according to Dr. Tomasetti and Dr. Vogelstein.
They then proceeded to attempt to distinguish the effect of this cell-replicative component from environmental and hereditary factors that contribute to the incidence of cancer. They defined an extra risk score (ERS) as the log product of the lifetime risk of cancer and the total number of stem cell divisions. They then used unsupervised machine learning methods to classify tumors based only on this score into two groups. The result was 9 tumors with high scores and 22 tumors with low ERS scores. If the ERS was high, it meant that there were added factors, such as heredity and environment, contributing to increase the cancer incidence. These they referred to as D-tumors (deterministic). If the ERS was low, that meant that stochastic factors during cell division were the main contributors to incidence, which they called R-tumors (replicative). Upon inspection, the D-tumors were indeed those that had been previously found to have a high hereditary or environmental component. A notable D-tumor, for example, was lung cancer in smokers, while lung cancer in nonsmokers was designated an R-tumor.
“These results have could have important public health implications,” the researchers indicated.
“The maximum fraction of tumors that are preventable through primary prevention (such as vaccines against infectious agents or altered lifestyle) may be evaluated from their ERS. For nonhereditary D-tumors, this fraction is high and primary prevention may make a major impact. ... For R-tumors, primary prevention measures are not likely to be effective, and secondary prevention should be the major focus,” Dr. Tomasetti and Dr. Vogelstein concluded.
The authors reported no relevant disclosures.