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Purpose: Tumors with mutations in the exonuclease domain of POLE are associated with ultrahigh mutation rates. POLE mutant tumors are best characterized in intestinal and uterine cancers and are associated with a prominent immune infiltrate and favorable prognosis. To determine whether mutations in other DNA polymerases cooperate with POLE mutations to generate the ultramutator phenotype, we analyzed exome sequence data from 15 cancer types with POLE mutations in The Cancer Genome Atlas (TCGA).Results: 36% of POLE mutant tumors, predominantly colorectal, stomach and endometrial cancers carried mutations in POLQ (E/Q) and/or POLZ/REV3L (E/Z). Mutation burden, microsatellite instability (MSI) status, tumor stage, disease free survival and immune scores were evaluated in these tumors. Compared to the POLE-only mutant tumors, tumors with E/Q, E/Z, and E/Q/Z mutations possessed significantly higher overall mutation frequencies (p < 0.001) and increased frequencies of mutations within the POLE exonuclease domain (p = 0.013). E/Q, E/Z, and E/Q/Z mutant colorectal, stomach and endometrial tumors within the TCGA cohort demonstrated 100% disease-free survival, even if mutations occurred outside the POLE exonuclease domain (p = 0.003). However, immune scores were related to microsatellite instability (MSI) and not POLE mutation status, suggesting that mechanisms in addition to host immune response may contribute to the prolonged disease-free survival.Conclusion: Our results demonstrate that POLE mutant tumors can be further substratified for outcomes prediction based on additional mutations in POLQ and ERV3L.