Multiple primary cancers as clues to environmental and heritable causes of cancer and mechanisms of carcinogenesis

Successes in cancer therapy are leading to an increasing incidence of second cancers, which may be due to the same factors that cause first cancers or to the effect of therapy for the first cancer. There are also a number of specific methodological and sampling problems that have to be controlled before informative studies can be embarked upon. The risk of a second cancer is higher than that for the first one, which may be an indication of a particular exposure, an inherited set of genes, or both. We show clustering of multiple cancers caused by tobacco, alcohol and infections. We discuss familial aggregation of cancer as one of the causes of multiple primary cancers. However, multiple primary cancers may particularly be a manifestation of polygenic susceptibility, which cannot easily be recognized as familial clustering, and multiple cancers may offer a model for understanding the complex etiology of human cancer and for generating and testing hypotheses on mechanisms of carcinogenesis.