In the 1970s and 1980s, clever scientific insight and innovation rapidly advanced our understanding of the molecular mechanisms of cancer biology. The discoveries of oncogenes and tumor suppressors, and the elucidation of their functions, greatly aided in studies aimed at a molecular understanding of the etiology of primary tumors. Despite this, cancer biologists had little understanding of the molecular aspects of metastasis. Considering the devastating consequences, scientists were anxious for a breakthrough. The first clue would come from the study of tumor suppressors.

Tumor suppressor genes were identified when it was discovered that their loss of function was critical to tumorigenesis. Prior to their discovery, researchers were of the mindset that the oncogenic phenotype was always dominant. In other words, a mutation need happen on only a single allele for a normal cell to be transformed into a tumor cell. However, not all disease incidence data seemed to fit neatly into this hypothesis. By studying retinoblastoma case histories, a “two-hit” hypothesis emerged, predicting that for at least some cancers, two mutations must occur (one on each allele) to successfully transform a cell [1]. Indeed, the retinoblastoma gene, or Rb, would become known as the first described tumor suppressor. We now know that the “two hits” need not come in the form of distinct somatic mutations but may be the result of any combination of germinal and/or somatic mutations, mitotic recombinations, gene conversions, and functional inactivation of genes owing to promoter hypermethylation.