The search for cancer risk factors: when can we stop looking?

In recent decades, countless cohort, case-control, and ecologic studies have been conducted in the search for cancer risk factors. On the basis of knowledge gained from these studies, various influential commentaries have endeavored to classify the extent to which the total cancer burden is attributable to general categories of risk, such as diet, tobacco, sun exposure, and others. These commentaries have led to the conventional wisdom that most of the cancer burden is caused by environmental factors and relatively little is directly attributable to genetic susceptibility. In the face of the apparent knowledge that the cancer burden is essentially fully "explainable" on the basis of known environmental risks, this article addresses the conceptual and empirical basis of the continued search for new risk factors. It proposes that the extent of the aggregation of cancer within individuals in the population--that is, the occurrence of second primary cancers--is a crucial statistic in this context. A study of the incidence of second primary melanoma suggests that the bulk of the risk variation in this disease cannot be explained by known risk factors. The implications of these ideas for research strategy and for public health policy are discussed.