Conclusions: 

Truncating MAP3K1/MAP2K4 alterations occur in nearly 2% of GI malignancy pts and are more commonly associated with dMMR/MSI-H, higher TMB and other immune biomarkers than WT. • In CRC, MAP3K1/MAP2K4-MT pts had a greater tendency for PIK3CA and APC co-mutation and significantly lower TP53 co-mutation versus WT pts; no difference was seen in BRAF V600E, ERBB2/ERBB3, or KRAS. • Potentially targetable co-mutation partners implicated in PI3K and MAPK pathways as well as POLE, BRCA2 and ATM warrant further evaluation, as well as a high co-mutation rate with ARID1A.