First description of ultramutated endometrial cancer caused by germline loss-of-function and somatic exonuclease domain mutations in POLE gene

Abstract Endometrial cancer (EC) harboring heterozygous POLE proofreading inactivating mutations (POLE-exo*) is associated with an increased number of somatic mutations that result in a distinctive anti-tumor immune response. However, the consequences of such POLE mutations in the context of the missing wild-type allele have not yet been described in endometrial tumors. A 72-year-old woman harboring a germline monoallelic frameshift mutation (p.Pro269fsTer26) in POLE was diagnosed with an EC having a somatic heterozygous mutation in the exonuclease domain of POLE (S459F). Targeted gene sequencing revealed an ultramutated phenotype (381 mutations/Mb) in the tumor and a 2-fold excess of mutations on the DNA leading strand. Additionally, we observed a mutational signature similar to the COSMIC signature 10, a higher mutation rate in this tumor than in endometrial tumors with heterozygous POLE-exo*, and an increased number of T lymphocytes. This is the first report of an ultramutated EC harboring a somatic POLE-exo* mutation in association with a germline loss-of-function mutation in this gene. The absence of a wild type POLE allele led to a particularly high mutational burden.