ABSTRACT
If either chance or environmental exposure was the dominant carcinogen, cancer risk would increase continuously with age, but it doesn’t. For all cancers studied, risk exhibits three phases: 1) Low risk at young ages, followed by 2) an increase in risk to a maximum at some later age, followed by 3) a plateau or decline in risk at advanced ages. Only a genetically-determined discontinuous process can explain this pattern. We analyzed differences in risk between tissues of tumor origin and between geographic locations, genders, races, and ethnicities for clues. Our analyses suggest that normal tissue differentiation is safe, but inadequate. At some critical age, regeneration or dedifferentiation is required and this is an invitation to carcinogenesis. Upon reaching this critical age, risk varies with the size of a target, which may correspond to the number of regenerating or dedifferentiating stem cells. Cancer incidence rates were analyzed for melanoma and cancers of the mouth, esophagus, stomach, small intestine, colon, rectum, liver, pancreas, larynx, bronchus, breast, and kidney in populations distributed worldwide and within the United States in two time eras. Over all cancers, in all populations, and both eras, the difference in age-specific rates between ages 50 and 40, d50-40, correlated strongly with age-standardized rates. Differences in d50-40 correlated strongly with differences in age-standardized rates between genders, races, and ethnicities. We suggest that, for the cancers studied, the critical age occurs between 40 and 50. If environmental exposure or segregating genes was the dominant carcinogen, the rank order of cancer risk between tissues of tumor origin would vary from one geographic location to another, because environment and segregating genes vary between geographic locations. Such variation was observed between rank order in Japan and rank order in other countries, but not between rank orders in the other countries. We suspect, therefore, that environment or segregating genes play an important role in determining the difference in rank order of risk for the tissues of tumor origin between Japan and other countries. If chance or environmental exposure was the dominant carcinogen, cancer risk would correlate strongly between pairs of cancers across populations, but it doesn’t. Coefficients of risk between pairs of cancers are, typically, moderate at best. Only mouth, larynx, bronchus, and kidney show strong coefficients. By our measures, cancer risk from aging exceeds cancer risk from other-than-aging causes in all populations in both eras. We suspect that the aging risk is determined by genes that are common to all members of our species, and we suggest that inhibiting tissue injury and unnecessary growth will reduce cancer risk.