Cancer causation: the Darwinian downside of past success?

Causal mechanisms in all diseases are diverse and multifactorial, but medical scientists, as pragmatists, inevitably focus on limited or circumscribed components of pathogenetic puzzles. In cancer, epidemiologists have traditionally sought to incriminate exposures; geneticists uncover inherited susceptibility; and molecular biologists deconstruct the proximal mechanisms of cell transformation. Molecular epidemiology promises to deliver new insights in terms of gene-environment interactions. Each of these endeavours has undeniably provided rich dividends and insights into cancer causation, but are these likely to be sufficient as a coherent explanation of our vulnerability to cancer? I suggest that the biological plausibility of causal mechanisms would benefit from a historical, evolutionary perspective. The essential argument is that genes or gene variants and phenotypic traits that were adaptively selected in the past as advantageous now contribute crucially to cancer because of their mismatch with current environmental and social circumstances. The risk at-tributes of skin pigmentation and some dietary factors in cancer can be plausibly interpreted within this context. A case is made here for a Darwinian perspective on breast and prostate cancers, for which current understanding of causation is limited and contentious.