Across CRC, IHCC, and PDAC, SMAD4 alterations were statistically more prevalent among homozygous MTAP-loss versus MTAP-intact GI cancers (PDAC [34.1% vs 24.6%, P < .0001]; IHCC [13.6% vs 6.6%, P < .0001]; CRC [24.2% vs 16.9%, P = .001]). Here, SMAD4 is linked to colorectal carcinoma.