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. 2015 Feb 1;121(3):386-94.
doi: 10.1002/cncr.29046. Epub 2014 Sep 15.

Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing

Caroline C Billingsley  1 , David E Cohn, David G Mutch, Julie A Stephens, Adrian A Suarez, Paul J Goodfellow
Affiliations

Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing

Caroline C Billingsley et al. Cancer. .

Abstract

Background: DNA polymerase ɛ (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE-mutant tumors were described as a molecular subtype with improved progression-free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC.

Methods: Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2-sided.

Results: Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years; P=.001). POLE mutations were detected in tumors with microsatellite stability (MSS) and microsatellite instability (MSI) at similar frequencies (5.9% and 5.2%, respectively) and were most common in tumors with MSI that lacked mutL homolog 1 (MLH1) methylation (P<.001). There was no association with progression-free survival (hazard ratio, 0.22; P=.127).

Conclusions: The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between POLE mutation and progression-free survival indicates that POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, POLE tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing.

Keywords: DNA mismatch repair; Lynch syndrome; endometrial cancer; mutation.

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Figures

Figure 1
Figure 1. POLE exonuclease domain mutations in endometrioid endometrial cancer cases
A) and B) are hotspot POLE mutations, C) and D) novel mutations, E) mutation previously seen in single colon cancer and F) an infrequent but known mutation.
Figure 2
Figure 2. Kaplan-Meier estimates according to POLE mutational status
A) Progression-free survival. B) Overall survival. P values calculated using log-rank test (two-sided).
Figure 3
Figure 3. Relationship POLE mutations, tumor microsatellite instability (MSI) and DNA mismatch repair (MMR) defects
Somatic POLE exonuclease domain mutations could phenocopy defective DNA mismatch repair (normal MMR but strand slippage mutations) or could lead to somatic inactivation of MMR genes with associated MSI and/or immunohistochemical (IHC) defect in tumors lacking MLH1 promoter methylation.
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