Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to the favorable survival of patients with tumors with POLE mutations outside the exonuclease domain

Fangjin Huang,Joanne K Rutgers,Hisashi Tanaka,Beatrice S Knudsen

doi:10.1186/s12881-020-01089-9

Fangjin Huang, Joanne K Rutgers + Show 2 more

Open Access

https://doi.org/10.1186/s12881-020-01089-9

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Abstract

BackgroundMutations 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.MethodsWe 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.ResultsThirty 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.ConclusionResults 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.

Highlights

Mutations in the exonuclease domain of Polymerase epsilon (POLE), a DNA polymerase associated with DNA replication and repair, lead to cancers with ultra-high mutation rates
14 cases with POLE and Polymerase theta (POLQ) mutations (E/Q), 16 cases with POLE and polymerase zeta (POLZ)/REV3L mutations (E/Z) and 20 cases with POLE, POLQ and POLZ/REV3L (E/Q/Z) mutations were identified in the PANCAN cohort (Fig. 1c)
In order to determine the contribution of POLQ and REV3L to the ultramutator phenotype, we compared the mutation frequencies of tumors with mutations in only POLE to E/Q, E/Z and E/Q/Z mutant tumors

Summary

Introduction

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. First identified and reported in 2–6% of colorectal carcinomas [2, 9, 10], POLE mutations were noted at frequencies of 6–9% amongst uterine corpus endometrial cancers [1, 11] and in gastric adenocarcinoma [12]. Mutations can be found across the entire POLE gene, but those in the POLE exonuclease domain are most prevalent in cancers with ultra-high mutation rates (> 100 mut/Mb). These cancers exhibit higher mutation rates than microsatellite instable (MSI) tumors associated with mismatch repair abnormalities. It is thought to be caused by neoantigens that are generated as a result of the high mutation burden [16, 17] and render POLE mutant cancers responsive to immunotherapy [18]

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