Milestones in Hereditary Colorectal Cancer Research

This reviews the historical evolution of our understanding of the familial gastrointestinal cancer syndromes. It begins centuries ago with the appreciation of the gastrointestinal polyposis syndromes and the relationship between adenomatous polyps and cancer. However, it was not until 1991 that the APC gene was cloned and linked to familial adenomatous polyposis. Mutated oncogenes and inactivated tumor suppressor genes were discovered in the 1970s, and it was appreciated by the late 1980s that these genetic alterations occurred sequentially during the evolution of gastrointestinal tumors. During the exploration of this process, it was unexpectedly recognized in the early 1990s that hereditary non-polyposis colorectal cancers had a specific mutational signature that was the result of inactivation of the DNA mismatch repair system. This disease involved a unique group of mutational targets, distinctive pathways to tumor development, and the remarkable recognition in the 21st century of novel and highly effective therapeutic approaches to tumor control. Mixed in with these discoveries was the appreciation of multiple unique hamartomatous polyposis syndromes. The progress made over the past 50 years is remarkable and highlights the rapid evolution of new technologies and insightful research.