Looking for the light at the end of the tunnel: elucidating hereditary colorectal cancer predisposition

It is well known that at least 5-10% of all cases of colorectal cancer (CRC) have a strong genetic component. To date, the discoveries of genes responsible for highly penetrant autosomal dominant CRC syndromes including Familial Adenomatous Polyposis (FAP), Lynch syndrome (LS), and the recessive syndrome MUTYH-Associated Polyposis (MAP), account for less than 5% of high risk CRC. A large fraction of the remaining high penetrant CRC syndrome(s) appears to be due to Familial Colorectal Cancer Type X (FCCTX), a recently coined term meant to describe likely genetically heterogeneous cases characterized by site-specific CRC without tumor high frequency microsatellite instability (microsatellite instability is the hallmark of LS). FCCTX kindreds are also characterized by somewhat lower lifetime risk of CRC, and no increased risk of extracolonic cancers (such as endometrial cancer), compared to LS. The identification of the genetic mechanism(s) responsible for FCCTX has important scientific and translational implications for understanding colorectal tumorigenesis and for applying tailored screening (colonoscopy) for subjects at high risk for CRC.