Background: Mutations in the exonuclease domain of POLE, a DNA polymerase associated with DNA replication and repair, lead to cancers with ultra-high mutation rates. Most studies focus on intestinal and uterine cancers with POLE mutations. These cancers exhibit a significant immune cell infiltrate and favorable prognosis. We questioned whether loss of function of other DNA polymerases can cooperate to POLE to generate the ultramutator phenotype.
Methods: We used cases and data from 15 cancer types in The Cancer Genome Atlas to investigate mutation frequencies of 14 different DNA polymerases. We tested whether tumor mutation burden, patient outcome (disease-free survival) and immune cell infiltration measured by ESTIMATE can be attributed to mutations in POLQ and POLZ/REV3L.
Results: Thirty six percent of colorectal, stomach and endometrial cancers with POLE mutations carried additional mutations in POLQ (E/Q), POLZ/REV3L (E/Z) or both DNA polymerases (E/Z/Q). The mutation burden in these tumors was significantly greater compared to POLE-only (E) mutant tumors (p < 0.001). In addition, E/Q, E/Z, and E/Q/Z mutant tumors possessed an increased frequency of mutations in the POLE exonuclease domain (p = 0.013). Colorectal, stomach and endometrial E/Q, E/Z, and E/Q/Z mutant tumors within TCGA demonstrated 100% disease-free survival, even if the POLE mutations occurred outside the exonuclease domain (p = 0.003). However, immune scores in these tumors were related to microsatellite instability (MSI) and not POLE mutation status. This suggests that the host immune response may not be the sole mechanism for prolonged disease-free survival of ultramutated tumors in this cohort.
Conclusion: Results in this study demonstrate that mutations in POLQ and REV3L in POLE mutant tumors should undergo further investigation to determine whether POLQ and REV3L mutations contribute to the ultramutator phenotype and favorable outcome of patients with POLE mutant tumors.