Pathogenic POLE-Mutated Endometrial Carcinomas With a Nonultramutated Genome
Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the POLE-mutant subtype carrying the best prognosis. Pathogenic mutations in POLE are known to disrupt the proofreading function of DNA polymerase epsilon, resulting in an ultramutated genome, typically defined as ≥100 mutations per megabase. Routine next-generation sequencing was implemented on all endometrial carcinoma cases at our institution beginning in December 2023 to aid in molecular subclassification. During this routine sequencing, 6 POLE-mutated cases, with confirmed pathogenic POLE mutations, were observed to have a tumor mutational burden <100; prior to universal testing, only 1 such case had been identified. Endometrial carcinoma cases with pathogenic POLE mutations and tumor mutational burden <100 may be globally under-recognized, as universal testing is not yet a widely standard practice. These cases with pathogenic POLE mutations and a nonultramutated genome were found to have a lower frequency of classic morphologic "POLE features," including high-grade histology, compared with classic ultramutated cases. The immunohistochemical profiles are also different from ultramutated counterparts, with a lower frequency of mismatch repair immunohistochemical abnormalities and p53 null or diffuse staining, and a higher likelihood of strong and diffuse estrogen receptor/progesterone receptor expression, aligning with fewer mutations in encoding genes. However, endometrial carcinoma with pathogenic POLE mutations, without ultramutation, appears to retain the "POLE-mutational signature" described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.