Taken collectively, 25% of GC tumors and 19% of colorectal cancer tumors are mutated in at least one of the 11 CBS hotspots. Overall, our analyses nominate these CBS hotspots as potentially common drivers of gastrointestinal cancers. Furthermore, the data supports a general link between CBS mutations and chromosomal instability. This suggests that non-coding regulatory mutations could potentially drive tumor evolution through interfacing with cancer genome and epigenome plasticity.