Mutations of the DNA polymerase epsilon (POLE) can lead to a hypermutated tumor phenotype, in the absence of microsatellite instability (MSI). Exceptional responses to ICPIs in POLE-mutated endometrial adenocarcinoma (EA), colorectal (CRC), and glioblastoma (GBM) are described, but detailed pan-tumor POLE analyses are lacking.
We prospectively analyzed 80,853 primarily advanced solid tumors using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11 Mb of sequenced DNA (PMID: 28420421). Known genomic alterations (kGA) were defined as those reported as somatic in the COSMIC database or with published evidence indicating loss of function.
POLE GA were identified in 5.0% of cases: melanoma (10%), duodenal adeno (DA, 7.8%), uterus carcinosarcoma (CS, 6.9%), EA (6.4%), unknown primary carcinoma (CUP, 6.3%), NSCLC (6.1%), CRC (5.1%), prostate adeno (5.0%), and GBM (4.6%). Most POLE GA were variants of unknown significance (VUS). POLE kGA were found in only 259 (0.3%) total cases, including ovary or uterus CS (2.2%), DA (1.3%), EA (1.2%), CRC (0.7%), GBM (0.6%), and CUP (0.6%). Patients with POLE kGA had a median age of 58 yrs (range 7-95); 53% were male. Median TMB in cases with POLE kGA, VUS and wild-type was 31, 9 and 3.6, respectively (each p 20), while 28% had low TMB (
POLE GA are found across tumor types, but functionally significant GA may be less frequent than previously reported, particularly in advanced tumors. Identification of specific POLE GA associated with a hypermutated phenotype may be important to identify likely responders to ICPIs.
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A.B. Schrock, D. Fabrizio, Y. He, J. Chung, P.J. Stephens, J.S. Ross, V.A. Miller, S. Ramkissoon, J.A. Elvin, S.M. Ali: Employee with stock ownership in Foundation Medicine. M. Resnick: Advisory board for PathAI. S.J. Klempner: Received honoraria from Foundation Medicine. All other authors have declared no conflicts of interest.