Gastrointestinal Polyposis Syndromes: Early Tumor Evolution Through the Looking Glass

Colorectal cancer has one of the highest famiLial associations of all human cancers. Although the majority of colorectal cancers occur outside the context of highly penetrant cancer-prone polyposis conditions, an increasing number of studies demonstrate that sporadic patients share genetic risk factors with famiLial cancer-prone patients, suggesting that there is no strict dichotomous separation between colorectal cancer in famiLial syndromes and sporadic patients. Predisposition to colorectal cancer may well show a normal distribution in the population with some patients affLicted by polyposis syndromes at the tail of this distribution and other patients (labeled 'sporadic') at the shoulder of this hypothetical bell curve. The genetic risk factors identified in cohorts of sporadic patients often intersect with defects in major risk alleles such as APC and SMAD4. This contribution focuses on recent developments in our understanding of the gastrointestinal polyposis syndromes of which the genetics have now been unraveled, concentrating on famiLial adenomatous polyposis. The quantitative analysis of precursor lesions in patients affLicted by famiLial colorectal cancer allows us to trace the clonal evolution of colorectal cancer from its earLiest beginnings. These exciting developments further emphasize that colorectal cancer is a heterogeneous, multipathway disease. Refinement of progression models within molecularly defined patient groups will allow us to provide accurate risk assessment for cancer-prone famiLies and sporadic patients aLike.