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. 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. 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. 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.

中文翻译：

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突变的 POLQ 和 POLZ/REV3L DNA 聚合酶可能有助于外切核酸酶结构域外具有 POLE 突变的肿瘤患者的良好生存。

POLE 是一种与 DNA 复制和修复相关的 DNA 聚合酶，其核酸外切酶结构域的突变会导致极高突变率的癌症。大多数研究重点关注具有 POLE 突变的肠道癌和子宫癌。这些癌症表现出显着的免疫细胞浸润和良好的预后。我们质疑其他 DNA 聚合酶功能的丧失是否可以与 POLE 配合产生超突变表型。我们使用癌症基因组图谱中 15 种癌症类型的病例和数据来研究 14 种不同 DNA 聚合酶的突变频率。我们测试了肿瘤突变负担、患者结果（无病生存）和通过 ESTIMATE 测量的免疫细胞浸润是否可归因于 POLQ 和 POLZ/REV3L 的突变。36% 具有 POLE 突变的结直肠癌、胃癌和子宫内膜癌携带 POLQ (E/Q)、POLZ/REV3L (E/Z) 或两种 DNA 聚合酶 (E/Z/Q) 的额外突变。与仅 POLE (E) 突变肿瘤相比，这些肿瘤的突变负担显着更大 (p < 0.001)。此外，E/Q、E/Z 和 E/Q/Z 突变肿瘤的 POLE 核酸外切酶结构域突变频率增加 (p = 0.013)。TCGA 内的结直肠、胃和子宫内膜 E/Q、E/Z 和 E/Q/Z 突变肿瘤表现出 100% 无病生存，即使 POLE 突变发生在核酸外切酶结构域之外 (p = 0.003)。然而，这些肿瘤的免疫评分与微卫星不稳定性 (MSI) 相关，而不是 POLE 突变状态。这表明宿主免疫反应可能不是该队列中超突变肿瘤延长无病生存的唯一机制。本研究的结果表明，POLE 突变肿瘤中 POLQ 和 REV3L 的突变应进行进一步研究，以确定 POLQ 和 REV3L 突变是否有助于 POLE 突变肿瘤患者的超突变表型和良好预后。