Biology of Precancers and Opportunities for Cancer Interception: Lesson from Colorectal Cancer Susceptibility Syndromes

Abstract Hereditary gastrointestinal cancer is associated with molecular and neoplastic precursors which have revealed much about sporadic carcinogenesis. Therefore, an appreciation of constitutional and somatic events linked to these syndromes have provided a useful model for the development of risk models and preventative strategies. In this review, we focus of two of the best characterized syndromes, Lynch syndrome (LS) and familial adenomatous polyposis (FAP). Our understanding of the neoplasia-immune interaction in LS has contributed to the development of immune mediated therapies including cancer preventing vaccines and immunotherapy for cancer precursors. Chemoprevention in LS with aspirin and nonsteroidal anti-inflammatory drugs has also translated into clinical cancer, however the efficacy of such agents in FAP remains elusive when cancer is applied as an endpoint in trials rather than the use of ‘indirect’ endpoints such as polyp burden, and requires further elucidation of biological mechanisms in FAP. Finally, we review controversies in gastrointestinal surveillance for LS and FAP, including limitations and opportunities of upper and lower gastrointestinal endoscopy in the prevention and early detection of cancer.