Taken collectively, 25% of all gastric tumors are mutated in at least one of the 11 CBS hotspots, representing the second most mutated functional region in GC after TP53 (50% of gastric tumors). To study if these hotspots could also play a role in other cancer types, we examined the recurrence of these 11 hotspots in 826 non-hypermutated tumors of 18 other cancer types5 (Fig. 6 and Supplementary Fig. 15). Strikingly, we found that 19% of colorectal cancer tumors were mutated at one or more of the CBS hotspots (Fig. 6a). Since colorectal cancer have pathological and molecular similarities to GC56, the CBS hotspot mutations may drive cancer progression in colorectal cancer through similar mechanisms as in GC. The CBS hotspots were mutated at lower frequencies in breast cancer, liver cancer, lung cancer, pancreas cancer, and lymphoma. Interestingly, while melanoma and bladder carcinoma also have high genome-wide mutation rates at CBS, none of the CBS hotspots were mutated in these two cancer types. Similarly, we found that mutations at all CBS hotspots had previously been reported in COSMIC57 or other genome-wide studies of gastrointestinal tumors15,40 (Supplementary Table 6). This suggests that the CBS hotspot mutations are generated and act in a cancer-specific manner.Fig. 6Pan-cancer analysis of mutation recurrence at the 11 CBS mutation hotspots. a Fraction of samples with mutation in at least one of the CBS hotspots in different cancer types. b Mutation rate of CBSs in different cancer types. c Mutation recurrence of individual CBS hotspots in different cancer types