Concurrent POLE hotspot mutations and mismatch repair deficiency/microsatellite instability in endometrial cancer: A challenge in molecular classification

Abstract

Objective

Endometrial carcinoma (EC) has different molecular subtypes associated with varied prognosis. We sought to characterize the molecular features of ECs with POLE hotspot mutations and concurrent mismatch repair (MMR) deficiency/high microsatellite instability (MSI).

Methods

We identified POLE-mutated (POLEmut), MMR-deficient (MMRd)/MSI-high (MSI-H), or combined POLEmut/MMRd ECs subjected to clinical tumor-normal panel sequencing between 2014 and 2023. Clonality of somatic mutations, MSI scoring, tumor mutational burden (TMB), proportion of somatic insertions and deletions (indels), and single base substitution (SBS) mutational signatures were extracted.

Results

We identified 41 ECs harboring POLE exonuclease domain hotspot mutations, 138 MMRd and/or MSI-H ECs, and 14 POLEmut/MMRd ECs. Among the 14 POLEmut/MMRd ECs, 11 (79 %) exhibited clonal POLE hotspot mutations; 4 (29 %) had a dominant POLE-related mutational signature, 4 (29 %) displayed dominant MMRd-related signatures, and 6 (43 %) had mixtures of POLE, aging/clock, MMRd, and POLEmut/MMRd-related SBS mutational signatures. The number of single nucleotide variants was higher in POLEmut/MMR-proficient (MMRp) and in POLEmut/MMRd ECs compared to POLE wild-type (wt)/MMRd EC (both p < 0.001). Small indels were enriched in POLEwt/MMRd ECs (p < 0.001). TMB was highest in POLEmut/MMRd EC compared to POLEmut/MMRp and POLEwt/MMRd ECs (both p < 0.001). Of 14 patients with POLEmut/MMRd EC, 21 % had a recurrence, versus 10 % of those with POLEmut/MMRp EC. Similar findings were noted in 3 POLEmut ECs in patients with Lynch syndrome; akin to somatic POLEmut ECs, these tumors had high TMB.

Conclusion

POLEmut/MMRd ECs may be genetically distinct. Further studies are needed to assess the impact on outcomes and treatment response within this population.