Polymerase ɛ (POLE) mutations in endometrial cancer: Clinical outcomes and implications for Lynch syndrome testing. Issue 3 (15th September 2014)

• Record Type: Journal Article
• Authors: Billingsley, Caroline C.; Cohn, David E.; Mutch, David G.; Stephens, Julie A.; Suarez, Adrian A.; Goodfellow, Paul J.
• Is Part Of: Cancer. Volume 121:Issue 3(2015)
• Page Start: 386
• Page End: 394
• Publication Date: 2014-09-15
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.29046
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr29046-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>DNA polymerase ɛ (<italic>POLE</italic>) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. <italic>POLE</italic>‐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 <italic>POLE</italic> mutations were investigated in patients with endometrioid EC.</p> </sec> <sec id="cncr29046-sec-0002" sec-type="section"> <title>METHODS</title> <p>Polymerase chain reaction amplification and Sanger sequencing were used to test for <italic>POLE</italic> mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2‐sided.</p> </sec> <sec id="cncr29046-sec-0003" sec-type="section"> <title>RESULTS</title> <p>Thirty <italic>POLE</italic> mutations (5.6%) were identified. Mutations were associated with younger age (<60 years; <italic>P</italic>=.001). <italic>POLE</italic> 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 (<italic>MLH1</italic>) methylation (<italic>P</italic><.001). There was no association with progression‐free survival (hazard ratio, 0.22; <italic>P</italic>=.127).</p> </sec> <sec id="cncr29046-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking <italic>MLH1</italic> methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that <italic>POLE</italic> mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between <italic>POLE</italic> mutation and progression‐free survival indicates that <italic>POLE</italic> mutation status is unlikely to be a clinically useful prognostic marker. However, <italic>POLE</italic> testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, <italic>POLE</italic> tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing. <bold><italic>Cancer</italic> 2015;121:386–394.</bold> © <italic>2014 American Cancer Society</italic>.</p> </sec> </abstract>